Journal articles on the topic 'Hypo dynamic heart'

BACKGROUND: Interval hypo-hyperoxic training is a new promising technology in medical rehabilitation, including the rehabilitation of patients with post-COVID syndrome. However, the mechanisms of therapeutic action of interval hypo-hyperoxic training in the recovery period after suffering COVID-19 have not been fully studied. The effectiveness of interval hypo-hyperoxic training largely depends on the method of interval hypo-hyperoxic training.
 AIM: to develop modes and study the effectiveness of the use of interval hypoxic training in patients with post-COVID syndrome.
 MATERIALS AND METHODS: The performed open randomized comparative study involved patients with a diagnosis of post-COVID syndrome ― "Condition after COVID-19" according to the ICD (code U09.9). Patients of the main group, against the background of a course of traditional rehabilitation treatment, received interval hypo-hyperoxic therapy from the OXYTERRA device. In the comparison group, patients received only a traditional course of rehabilitation treatment. The study was conducted for 4 months. To assess the effectiveness of interval hypo-hyperoxic training before and after the course of rehabilitation, we studied the dynamics of the parameters of the circulatory system and the function of external respiration.
 RESULTS: 50 patients (19 women, 31 men, mean age 61.77.7 years) were randomly divided into the main group (n=30) and the comparison group (n=20). All patients completed a full course of rehabilitation. It was established that the course of training with interval hypo-hyperoxic training contributed to an increase in the oxygen capacity of the blood, an increase in the oxygen content in arterial blood, a decrease in heart rate, normalization of the level of systolic and diastolic pressure, restoration of stroke and minute blood volume parameters in patients of the main group. Interval hypo-hyperoxic training caused an improvement in the functional state of the bronchopulmonary system (p 0.049). There was an improvement in the activity of the central ergotropic and humoral-metabolic mechanisms of heart rhythm regulation, correction of the activity of the sympathetic link of regulation and the modulating effect of the parasympathetic division on the heart rhythm, normalization of the vagosympathetic balance coefficient.
 CONCLUSION: The use of interval hypo-hyperoxic training in the recovery period in patients with post-COVID syndrome according to the developed method caused a stable improvement in the clinical condition, which lasted from 3 to 6 months after the completion of complex rehabilitation.

Glucose metabolism in the heart requires oxidation of cytosolic NADH from glycolysis. This study examines shuttling reducing equivalents from the cytosol to the mitochondria via the activity and expression of the oxoglutarate-malate carrier (OMC) in rat hearts subjected to 2 wk (Hyp2, n = 6) and 10 wk (Hyp10, n = 8) of pressure overload hypertrophy vs. that of sham-operated rats (Sham2, n = 6; and Sham10, n = 7). Moderate aortic banding produced increased atrial natriuretic factor (ANF) mRNA expression at 2 and 10 wk, but only at 10 wk did hearts develop compensatory hypertrophy (33% increase, P < 0.05). Isolated hearts were perfused with the short-chain fatty acid [2,4-13C2]butyrate (2 mM) and glucose (5 mM) to enable dynamic-mode 13C NMR of intermediate exchange across OMC. OMC flux increased before the development of hypertrophy: Hyp2 = 9.6 ± 2.1 vs. Sham2 = 3.7 ± 1.2 μM·min−1·g dry wt−1, providing an increased contribution of cytosolic NADH to energy synthesis in the mitochondria. With compensatory hypertrophy, OMC flux returned to normal: Hyp10 = 3.9 ± 1.7 vs. Sham10 = 3.8 ± 1.2 μM·g−1·min−1. Despite changes in activity, no differences in OMC expression occurred between Hyp and Sham groups. Elevated OMC flux represented augmented cytosolic NADH shuttling, coupled to increased nonoxidative glycolysis, in response to hypertrophic stimulus. However, development of compensatory hypertrophy moderated the pressure-induced elevation in OMC flux, which returned to control levels. The findings indicate that the challenge of pressure overload increases cytosolic redox state and its contribution to mitochondrial oxidation but that hypertrophy, before decompensation, alleviates this stress response.

Background: Oxidative stress in cardiac disease promotes proarrhythmic disturbances in Ca 2+ homeostasis, impairing luminal Ca 2+ regulation of the sarcoplasmic reticulum (SR) Ca 2+ release channel, the RyR2 (ryanodine receptor), and increasing channel activity. However, exact mechanisms underlying redox-mediated increase of RyR2 function in cardiac disease remain elusive. We tested whether the oxidoreductase family of proteins that dynamically regulate the oxidative environment within the SR are involved in this process. Methods: A rat model of hypertrophy induced by thoracic aortic banding (TAB) was used for ex vivo whole heart optical mapping and for Ca 2+ and reactive oxygen species imaging in isolated ventricular myocytes (VMs). Results: The SR-targeted reactive oxygen species biosensor ERroGFP showed increased intra-SR oxidation in TAB VMs that was associated with increased expression of Ero1α (endoplasmic reticulum oxidoreductase 1 alpha). Pharmacological (EN460) or genetic Ero1α inhibition normalized SR redox state, increased Ca 2+ transient amplitude and SR Ca 2+ content, and reduced proarrhythmic spontaneous Ca 2+ waves in TAB VMs under β-adrenergic stimulation (isoproterenol). Ero1α overexpression in Sham VMs had opposite effects. Ero1α inhibition attenuated Ca 2+ -dependent ventricular tachyarrhythmias in TAB hearts challenged with isoproterenol. Experiments in TAB VMs and human embryonic kidney 293 cells expressing human RyR2 revealed that an Ero1α-mediated increase in SR Ca 2+ -channel activity involves dissociation of intraluminal protein ERp44 (endoplasmic reticulum protein 44) from the RyR2 complex. Site-directed mutagenesis and molecular dynamics simulations demonstrated a novel redox-sensitive association of ERp44 with RyR2 mediated by intraluminal cysteine 4806. ERp44-RyR2 association in TAB VMs was restored by Ero1α inhibition, but not by reducing agent dithiothreitol, as hypo-oxidation precludes formation of covalent bond between RyR2 and ERp44. Conclusions: A novel axis of intraluminal interaction between RyR2, ERp44, and Ero1α has been identified. Ero1α inhibition exhibits promising therapeutic potential by stabilizing RyR2-ERp44 complex, thereby reducing spontaneous Ca 2+ release and Ca 2+ -dependent tachyarrhythmias in hypertrophic hearts, without causing hypo-oxidative stress in the SR.

The purpose of the study was to examine the features of heart rate variability in experimental hyper- and hypofunction of the pineal gland, complicated by adrenal myocardial dystrophy. Materials and methods. To solve the set tasks, three models of functional states were created: hypo-, hyperfunction of the pineal gland, adrenaline myocardial dystrophy. Hypermelatoninemia was reproduced by administering melatonin. The hypofunction of the pineal gland was simulated by round-the-clock lighting. An experimental model of cardiac pathology, namely adrenaline myocardial dystrophy, was reproduced by administering adrenaline hydrochloride. The degree of tension of regulatory mechanisms and mechanisms of nervous regulation was assessed by mathematical analysis of heart rate variability. Results and discussion. The task of mathematical analysis is to extract “hidden information” and thereby assess the state and degree of tension of the regulatory mechanisms of the whole organism. According to the authors, mathematical analysis allows a differentiated approach to the assessment of regulatory effects, which is done by the nervous autonomic system, subcortical structures and the cerebral cortex. The data obtained by the authors suggest that the introduction of adrenaline in conditions of hypofunction of the pineal gland have cause-and-effect changes. These changes lead to disorders of autonomic regulation and possibly a trigger mechanism for a decrease in melatonin production by the pineal gland. Studies have shown that one of the advantages in conditions of hyperfunction of the pineal gland is the dominant role of parasympathetic processes in the mechanisms of adaptation of the heart to conditions of adrenal myocardial dystrophy. Timely and sufficient activation of melatonin provides a high efficiency of compensatory-adaptive changes and a positive role in increasing myocardial resistance. Conclusion. The results of the study showed that the dynamics of changes in the values of the indicators of the mathematical analysis of the heart rate in adrenal myocardial dystrophy against the background of hypo- and hyperfunction of the pineal gland revealed unidirectional changes. These changes are manifested in a decrease in heart rate, stress index and vegetative balance indicator. Consequently, the results obtained suggest that the introduction of melatonin against the background of adrenal myocardial dystrophy has a general corrective effect on the restoration of the functional state of the heart. Based on the results, the authors consider it appropriate to continue the study of the influence of various stressors on the functional state of the heart in conditions of different physiological activity of the pineal gland

Features of the heart rate variability at patients with acute disorder of cerebral circulation depending on the type of hemodynamics were studied in acute period of disease and in a condition of relative functional rest. Surveyed men and women (121 patients, 3055 years old) were divided into 3 groups according to the type of hemodynamics that was defined at the first day of their disease: the groups of patients with hyper-, hypo- and normodynamic types of hemodynamics were selected. The integral rheography of the body was carried out again on the 7th day of hospitalization of the patients. And according to the received data all examined individuals were divided into subgroups. The evaluation of indicators of the heart rate variability at patients during acute period of disease showed the significant increase of activity of the sympathetic link of regulation among people with hyperdynamic type of hemodynamics: the indices of tension and vegetative balance also as the standard deviation of NN intervals (SDNN) were rather law. The sam e patients examined on the 7th day of their disease demonstrated the reduction of the indices of tension and vegetative balance and the increase of the mean square difference between the duration of adjacent R-R intervals (RMSSD). These changes were regarded as gradual weakening of the sympathetic influences on cardio-vascular system in stabilization period. At examination of patients in a week from the moment of their hospitalization transformation of the type of hemodynamics was revealed among many of the surveyed. The indices of tension and vegetative balance were the lowest among patients with acute disorder of cerebral circulation and initially hyperdynamic type of hemodynamics and newly formed hypodynamic type of blood circulation. While patients with acute disorder of cerebral circulation and constantly hyperdynamic type of blood circulation showed the maximal tension in operation of the regulatory systems.

Introduction: Human morphology and physiology are not designed inherently to function in microgravity. Hence, exposure to hypo or microgravity, as it occurs during space exploration, poses challenges in the form of peculiar adaptive physiological processes in healthy astronauts. These changes may vary (to a certain extent) depending on type of physical fitness (namely, aerobic or anaerobic) and may have definitive impact on short duration space mission. The study aimed to examine the cardiovascular dynamics during short duration exposure to simulated microgravity condition in differently trained individuals. Material and Methods: Temporal variations in body fluid distribution were studied during 6° head-down tilt (HDT) for 4-hours in 31 healthy males in age range of 20–40 years divided into three groups based on their physical training, namely; resistance trained (RT), endurance trained (ET), and untrained (UT). This was based on their history of physical training, VO2 max, and peak anaerobic power. Results: Heart rate in the ET group and RT group showed increasing and decreasing trend respectively, however, statistically remained non-significant. Systolic and diastolic pressures showed a significant increase in the ET group at the 4th h of HDT as compared to baseline and the 1st h. No significant variation in pulse pressure could be seen. Mean arterial pressures showed significant increase in the ET group at the 4th h of HDT as compared to baseline and the 1st h of HDT. Stroke volume and cardiac output did not vary significantly. Conclusion: ET individuals in the present study demonstrated decreased sensitivity of baroreceptors than RT or UT individuals, whereas, the RT group demonstrated more stability/resilience in terms of cardiovascular dynamics than ET and UT groups under exposure to short duration simulated microgravity.

Purpose The purpose of this study is to navigate the challenges irregular migratory flows generate for cities and urban systems. The migration and refugee crises that challenged Europe in 2015-2016 revealed that the developed world cities and urban areas are largely unprepared to address challenges that irregular migratory flows generate. This paper queries the smart and resilient cities’ debates, respectively, to highlight that migration-related challenges and opportunities have not been explicitly addressed in those deliberations. This creates a disconnect between what these debates promise and what cities/urban systems increasingly need to address on a daily basis. Subsequently, a way of bridging that disconnect is proposed and its policy-making implications discussed. Design/methodology/approach To suggest ways of navigating irregular migration-inflicted challenges cities/urban areas face, a nexus between the smart cities and resilient cities’ debates is established. By placing advanced sophisticated information and communication technologies (ICTs) at the heart of the analysis, a novel dynamic ICTs’ enabled integrated framework for resilient urban systems is developed. The framework’s dynamics is defined by two hierarchically interconnected levers, i.e. that of ICTs and that of policy-design and policy-making. Drawing from qualitative analysis and process tracing, the cross-section of policy design and policy-making geared towards the most efficient and ethically sensitive use of sophisticated ICTs is queried. Subsequently, options available to cities/urban systems are discussed. Findings The ICTs’ enabled integrated framework for resilient urban systems integrates the effectiveness of migrants and refugees’ policy design and policy-making in human-centred thinking, planning and policy-design for resilient urban systems. It places resilient approaches in the spotlight of research and policy-making, naming them the most effective methods for promoting a humanistic smart cities and resilient urban systems vision. It highlights critical junctions that urban systems’ stakeholders must consider if the promise of emerging sophisticated ICTs is to be employed effectively for the entire society, including its most vulnerable members. Research limitations/implications First, when designing ICTs’ enabled integrated resilient urban systems, the key stakeholders involved in the policy-design and policy-making process, including local, national and regional authorities, must employ a holistic view to the urban systems seen through the lens of hard and soft concerns as well as considerations expressed by the receiving and incoming populations. Second, the third-sector representatives, including non-governmental organizations (NGOs) and other actors, need to be seen as peers in integrated humanistic networks, thereby contributing critical, unbiased knowledge flows to infrastructures, which promote fair and inclusive participation of migrants and refugees in local economies. Practical implications The ICTs’ enabled integrated framework for resilient urban systems promotes a humanistic smart cities’ and resilient urban systems’ vision. It suggests how to design and implement policies apt to meet the needs of both receiving and incoming populations along value chains specific to smart and resilient cities. It promotes emerging sophisticated ICTs as the subtle, yet key, enabler of data ecosystems and customized services capable of responding to critical societal needs of the receiving and the incoming populations. In addition, the framework suggests options, alternatives and strategies for urban systems’ stakeholders, including the authorities, businesses, NGOs, inhabitants and ICTs’ providers and vendors. Originality/value The value added of this paper is three-fold. At the conceptual level, by bringing together the smart cities and resilient cities debates, and incorporating sophisticated ICTs in the analysis, it makes a case for their usefulness for cities/urban areas in light of challenges these cities/urban areas confront each day. At the empirical level, this analysis maps the key challenges that cities and their stakeholders face in context of migratory flows and highlights their dual nature. At the policy-making level, this study makes a case for a sound set of policies and actions that boost effective use of ICTs beyond the smart technology hype.

In this era of startling developments in the medical field there remains a serious worry about the hazardous potential of various by products which if not properly addressed can lead to consequences of immense public concern. Hospitals and other health care facilities generate waste products which are evidently hazardous to all those exposed to its potentially harmful effects. Need for effective legislation ensuring its safe disposal is supposed to be an integral part of any country's health related policy. This issue is of special importance in developing countries like Pakistan which in spite of framing various regulations for safeguarding public health, seem to overlook its actual implementation. The result unfortunately is the price wehave to pay not only in terms of rampant spread of crippling infections but a significant spending of health budget on combating epidemics which could easily have been avoided through effective waste disposal measures in the first place. Waste classified under the heading 'bio-hazardous' includes any infectious or potentially infectious material which can be injurious or harmful to humans and other living organisms. Amongst the many potential sources are the hospitals or other health delivery centres which are ironically supposed to be the centres of infection control and treatment. Whilst working in these setups, health care workers such as doctors, nurses, paramedical staff and sanitation workers are actually the ones most exposed and vulnerable to these challenges. Biomedical waste may broadly be classified into Infectious and toxic waste. Infectious waste includes sharps, blood, body fluids and tissues etcwhile substances such as radioactive material and by-products of certain drugs qualify as toxic waste. Furthermore health institutions also have to cater for general municipal waste such as carton boxes, paper and plastics. The World Health Organisation has its own general classification of hospital waste divided into almost eight categories of which almost 15% (10% infectious and 5% toxic) is estimated to be of a hazardous nature while the remaining 85% is general non hazardous content.1A recent study from Faisalabad, Pakistan has estimated hospital waste generation around 1 to 1.5 kg / bed /day for public sector hospitals in the region,2while figures quoted from neighbouring India are approximately 0.5 to 2 KG / hospital bed /day.3 Elsewhere in the world variable daily hospital waste production has been observed ranging from as low as 0.14 to 0.49 kg /day in Korea4 and 0.26 to 0.89 kg/day in Greece5to as high as 2.1 to 3.83 kg/day in Turkey6 and 0.84 to 5.8 kg/day in Tanzania.7Ill effects of improper management of hospital waste can manifest as nosocomial infections or occupational hazards such as needle stick injuries. Pathogens or spores can be borne either through the oro-faecal or respiratory routes in addition to direct inoculation through contact with infected needles or sharps. Environmental pollution can result from improper burning of toxic material leading to emission of dioxins, particulate matter or furans into the air. The habitat can also be affected by illegal dumping and landfills or washing up of medical waste released into the sea or river. Potential organisms implicated in diseases secondary to mismanagement of hospital waste disposal include salmonella, cholera, shigella, helminths, strep pneumonia, measles, tuberculosis, herpesvirus, anthrax, meningitis, HIV, hepatitis and candida etc. These infections can cause a considerable strain on the overall health and finances of the community or individuals affected. The basic principal of Public health management i.e 'prevention is better than cure' cannot be more stressed in this scenario as compared to any other health challenge. Health facilities must have a clear policy on hazardous waste management. To ensure a safe environment hospitals need to adopt and implement international and local systems of waste disposal. Hospital waste management plan entails policy and procedures addressing waste generation, accumulation, handling, transportation, storage, treatment and disposal. Waste needs to be collected in marked containers usually colour coded and leak proof. Segregation at source is of vital importance. The standard practice in many countries is the Basic Three Bin System ie to segregate the waste into RED bags/ boxes for sharps, YELLOW bags for biological waste and BLUE or BLACK ones for general/ municipal waste. All hospital staff needs to be trained in the concept of putting the right waste in relevant containers/ bags. They need to know that more than anything else this practice is vital for their own safety. The message can be reinforced through appropriate labelling on the bins and having posters with simple delineations to avoid mixing of different waste types. Sharps essentially should be kept in rigid, leak and puncture-resistant containers which are tightly lidded and labelled. Regular training sessions for nurses and cleaning staff can be organised as they are the personnel who are more likely to deal with waste disposition at the level of their respective departments. Next of course is transportation of waste products to the storage or disposal. Sanitary staff and janitors must be aware of the basic concepts of waste handling and should wear protective clothing, masks and gloves etc, besides ensuring regular practice of disinfection and sterilization techniques.8Special trolleys or vehicles exclusively designed and reserved for biomedical waste and operated by trained individuals should be used for transportation to the dumping or treatment site. Biomedical waste treatment whether on site or off site is a specialised entity involving use of chemicals and equipment intended for curtailing the hazardous potential of the material at hand. Thermal treatment via incinerators, not only results in combustion of organic substances but the final product in the form of non-toxicash is only 10 to 15% of the original solid mass of waste material fed to the machine. Dedicated autoclaves and microwaves can also be used for the purpose of disinfection. Chemicals such as bleach, sodium hydroxides, chlorine dioxide and sodiumhypochlorite are also effective disinfectants having specialised indications. Countries around the world have their own regulations for waste management. United Kingdom practices strict observance of Environmental protection act 1990, Waste managementlicensing regulations 1994 and Hazardous waste regulations 2005 making it one of thesafest countries in terms of hazardous waste disposal. Similar regulations specific for each state have been adopted in United States following passage of the Medical Waste tracking act 1988. In Pakistan, every hospital must comply with the Waste Management Rules 2005 (Environment Protection Act 1997), though actual compliance is far from satisfactory. It is high time that the government and responsible community organisations shape up to seriously tackle the issue of bio hazardous waste management through enforcement of effective policies and standard operating procedures for safeguarding the health and lives of the public in general and health workers in particular.
 Outbreaks, defined as excess cases of a particular disease or illness which outweighs the response capabilities, have the capacity to overwhelm health care facilities and need timely response and attention to details in order to avoid potentially disastrous sequelae . In this day and age when improvement in public health practices have significantly curtailed outbreak of various diseases, certain viral illnesses continue to make headlines. One of the notable vector borne infectious disease affecting significant portions of south east Asia in the early part of twenty first century is 'Dengue fever'. Dreaded as it is by those suffering from the illness, a lot of the hysteria created is secondary to a lack of education and understanding of the nature of the disease and at times a result of disinformation campaign for vested interests by certain political and media sections.'Dengue' in fact is a Spanish word, assumed to have originated from the Swahili phrase -ka dinga peppo -which describes the disease as being caused by evil spirit. 1 Over the course of time it has been called 'breakbone fever', 'bilious vomiting fever', 'break heart fever', 'dandy fever', 'la dengue' and 'Phillipine, Thai and Singapore hemorrhagic fever' Whilst the first reported case referring to dengue fever as a water poison spread by flying insects, exists in the Chinese medical encyclopedia from Jin Dynasty (265-420 AD), the disease is believed to have disseminated from Africa with the spread of the primary vector, aedes egypti, in the 15th to 19th century as a result of globalisation of slave trade 45In 80% of the patients affected by this condition the presentation is rather insidious and at best characterized by mild fever. The classical 'Dengue fever' present in about 5% of the cases is characterized by high temperature, body aches, vomiting and at times a skin rash. The disease may regresses in two to seven days. However inrare instances (<5%) it may develop into more serious conditions such as Dengue hemorrhagic fever whereby the platelet count is significantly reduced leading to bleeding tendencies and may even culminate in a more life threatening presentation i.e Dengue shock syndrome.6To understand the actual dynamics of Dengue epidemic it is important to understand the mode of its spread in affected areas. Aedes mosquito (significantly Aedes Egypti) acts a vector for this disease. Early morning and evening times7 are favoured by these mosquitos to feed on their prey. There is some evidence that the disease may be transmitted via blood products and organ donation. 8 Moreover vertical transmission (mother to child) has also been reported 9Diagnostic investigations include blood antigen detection through NS-I or nucleic acid detection via PCR. IO Cell cultures and specific serology may also be used for confirming the underlying disease. Whilst sporadic and endemic cases are part of routine medical practice and may not raise any alarm bells, outbreaks certainly need mobilization of appropriate resources for effective control. Needless to say 'prevention is better than cure' and should be the primary target of the health authorities in devising strategies for disease control.The WHO recommended 'Integrated Vector control programme', lays stress on social mobilisation and strengthening of public health bodies, coherent response of health and related departments and effective capacity building of relevant personnel and organisations as well as the community at risk. For Aedes Egypti the primary control revolves around eliminating its habitats such as open sources of water. In a local perspective in our city Peshawar, venue of the recent dengue epidemic, it may be seen in the form of incidental reservoirs such as receptacles and tyres dumped in open areas such as roof tops with rain water accumulating in them and provtdjng excellent breeding habitats, Larvicidal and insecticides may be added to more permanent sources such as watertanks and farm lands. There is not much of a role for spraying with organophosphorous agents which is at times resorted to for public consumption. Public education is the key to any effective strategy which must highlight the need for wearing clothing that fully covers the skin, avoiding unnecessary early morning and evening exposure to vector agents, application of insect repellents and use of mosquito nets. It is also important not to panic if affliction with the disease is suspected as in a vast majority of instances it is a self limiting illness without any long term harmful effects and needs simple conservative management like antipyretics and analgesics.An important consideration for responsible authorities in a dengue epidemic is to ensure that maximum management facilities for simple cases are provided at the community level through primary and secondary health care facilities and that the tertiary care hospitals are not inundated with all sort of patients demanding consultation. These later facilities should be reserved for those patients who end up with any complications or more severe manifestation of the disease.Research is underway to develop an ideal vaccine for Dengue fever. In 2016, a vaccine by the name 'Dengvaxia' was marketed in Phillipines and Indonesia. However with development of new serotypes of the virus, its efficacy has been somewhat compromised.As for treatment , there are no specific antiviral drugs. Management is symptomatic revolving mainly around oral and intravenous hydration. Paracetamol (Acetaminophen) is used for fever as compared to NSAIDS such as Ibuprophen infusion as well as blood and platelet transfusion.Data to date shows that slightly more than twenty three thousand people have been diagnosed with dengue over the past three months ie August to October there is a lower risk of bleeding with the former. Those with more severe form of the disease may need Dextran 2017, in Peshawar, Pakistan with around fourteen thousand needing admission and about sixty nine recorded deaths. The mortality is well within the acceptable international standards of less than 1% for the disease. In the backdrop of all the debate surrounding the current epidemic, one can infer that such outbreaks are best addressed with effective planningwell ahead of the time before the disease threatens to spiral out of control. Simple measures such as covering water storage facilities, using larvicidals where practical, use of insect repellents, mosquito nets and avoiding unnecessary exposure can offerthe best protection. Public health messages via print and electronic media can help educate people in affected areas and allay any anxiety building up from a fear of developing life threatening complications. Health department must mobilise all its resources to ensure local management of diagnosed patients with simple dengue fever and facilitate hospital admission only for those suffering from more severe form of the disease. Moreover the media hype into such situations needs to be addressed through constant updates and discouraging any negative politicking on the issue. To sum up Dengue fever is not really an affliction to be dreaded provided it is viewed and managed in the right perspective.

In this era of startling developments in the medical field there remains a serious worry about the hazardous potential of various by products which if not properly addressed can lead to consequences of immense public concern. Hospitals and other health care facilities generate waste products which are evidently hazardous to all those exposed to its potentially harmful effects. Need for effective legislation ensuring its safe disposal is supposed to be an integral part of any country's health related policy. This issue is of special importance in developing countries like Pakistan which in spite of framing various regulations for safeguarding public health, seem to overlook its actual implementation. The result unfortunately is the price wehave to pay not only in terms of rampant spread of crippling infections but a significant spending of health budget on combating epidemics which could easily have been avoided through effective waste disposal measures in the first place. Waste classified under the heading 'bio-hazardous' includes any infectious or potentially infectious material which can be injurious or harmful to humans and other living organisms. Amongst the many potential sources are the hospitals or other health delivery centres which are ironically supposed to be the centres of infection control and treatment. Whilst working in these setups, health care workers such as doctors, nurses, paramedical staff and sanitation workers are actually the ones most exposed and vulnerable to these challenges. Biomedical waste may broadly be classified into Infectious and toxic waste. Infectious waste includes sharps, blood, body fluids and tissues etcwhile substances such as radioactive material and by-products of certain drugs qualify as toxic waste. Furthermore health institutions also have to cater for general municipal waste such as carton boxes, paper and plastics. The World Health Organisation has its own general classification of hospital waste divided into almost eight categories of which almost 15% (10% infectious and 5% toxic) is estimated to be of a hazardous nature while the remaining 85% is general non hazardous content.1A recent study from Faisalabad, Pakistan has estimated hospital waste generation around 1 to 1.5 kg / bed /day for public sector hospitals in the region,2while figures quoted from neighbouring India are approximately 0.5 to 2 KG / hospital bed /day.3 Elsewhere in the world variable daily hospital waste production has been observed ranging from as low as 0.14 to 0.49 kg /day in Korea4 and 0.26 to 0.89 kg/day in Greece5to as high as 2.1 to 3.83 kg/day in Turkey6 and 0.84 to 5.8 kg/day in Tanzania.7Ill effects of improper management of hospital waste can manifest as nosocomial infections or occupational hazards such as needle stick injuries. Pathogens or spores can be borne either through the oro-faecal or respiratory routes in addition to direct inoculation through contact with infected needles or sharps. Environmental pollution can result from improper burning of toxic material leading to emission of dioxins, particulate matter or furans into the air. The habitat can also be affected by illegal dumping and landfills or washing up of medical waste released into the sea or river. Potential organisms implicated in diseases secondary to mismanagement of hospital waste disposal include salmonella, cholera, shigella, helminths, strep pneumonia, measles, tuberculosis, herpesvirus, anthrax, meningitis, HIV, hepatitis and candida etc. These infections can cause a considerable strain on the overall health and finances of the community or individuals affected. The basic principal of Public health management i.e 'prevention is better than cure' cannot be more stressed in this scenario as compared to any other health challenge. Health facilities must have a clear policy on hazardous waste management. To ensure a safe environment hospitals need to adopt and implement international and local systems of waste disposal. Hospital waste management plan entails policy and procedures addressing waste generation, accumulation, handling, transportation, storage, treatment and disposal. Waste needs to be collected in marked containers usually colour coded and leak proof. Segregation at source is of vital importance. The standard practice in many countries is the Basic Three Bin System ie to segregate the waste into RED bags/ boxes for sharps, YELLOW bags for biological waste and BLUE or BLACK ones for general/ municipal waste. All hospital staff needs to be trained in the concept of putting the right waste in relevant containers/ bags. They need to know that more than anything else this practice is vital for their own safety. The message can be reinforced through appropriate labelling on the bins and having posters with simple delineations to avoid mixing of different waste types. Sharps essentially should be kept in rigid, leak and puncture-resistant containers which are tightly lidded and labelled. Regular training sessions for nurses and cleaning staff can be organised as they are the personnel who are more likely to deal with waste disposition at the level of their respective departments. Next of course is transportation of waste products to the storage or disposal. Sanitary staff and janitors must be aware of the basic concepts of waste handling and should wear protective clothing, masks and gloves etc, besides ensuring regular practice of disinfection and sterilization techniques.8Special trolleys or vehicles exclusively designed and reserved for biomedical waste and operated by trained individuals should be used for transportation to the dumping or treatment site. Biomedical waste treatment whether on site or off site is a specialised entity involving use of chemicals and equipment intended for curtailing the hazardous potential of the material at hand. Thermal treatment via incinerators, not only results in combustion of organic substances but the final product in the form of non-toxicash is only 10 to 15% of the original solid mass of waste material fed to the machine. Dedicated autoclaves and microwaves can also be used for the purpose of disinfection. Chemicals such as bleach, sodium hydroxides, chlorine dioxide and sodiumhypochlorite are also effective disinfectants having specialised indications. Countries around the world have their own regulations for waste management. United Kingdom practices strict observance of Environmental protection act 1990, Waste managementlicensing regulations 1994 and Hazardous waste regulations 2005 making it one of thesafest countries in terms of hazardous waste disposal. Similar regulations specific for each state have been adopted in United States following passage of the Medical Waste tracking act 1988. In Pakistan, every hospital must comply with the Waste Management Rules 2005 (Environment Protection Act 1997), though actual compliance is far from satisfactory. It is high time that the government and responsible community organisations shape up to seriously tackle the issue of bio hazardous waste management through enforcement of effective policies and standard operating procedures for safeguarding the health and lives of the public in general and health workers in particular.
 Outbreaks, defined as excess cases of a particular disease or illness which outweighs the response capabilities, have the capacity to overwhelm health care facilities and need timely response and attention to details in order to avoid potentially disastrous sequelae . In this day and age when improvement in public health practices have significantly curtailed outbreak of various diseases, certain viral illnesses continue to make headlines. One of the notable vector borne infectious disease affecting significant portions of south east Asia in the early part of twenty first century is 'Dengue fever'. Dreaded as it is by those suffering from the illness, a lot of the hysteria created is secondary to a lack of education and understanding of the nature of the disease and at times a result of disinformation campaign for vested interests by certain political and media sections.'Dengue' in fact is a Spanish word, assumed to have originated from the Swahili phrase -ka dinga peppo -which describes the disease as being caused by evil spirit. 1 Over the course of time it has been called 'breakbone fever', 'bilious vomiting fever', 'break heart fever', 'dandy fever', 'la dengue' and 'Phillipine, Thai and Singapore hemorrhagic fever' Whilst the first reported case referring to dengue fever as a water poison spread by flying insects, exists in the Chinese medical encyclopedia from Jin Dynasty (265-420 AD), the disease is believed to have disseminated from Africa with the spread of the primary vector, aedes egypti, in the 15th to 19th century as a result of globalisation of slave trade 45In 80% of the patients affected by this condition the presentation is rather insidious and at best characterized by mild fever. The classical 'Dengue fever' present in about 5% of the cases is characterized by high temperature, body aches, vomiting and at times a skin rash. The disease may regresses in two to seven days. However inrare instances (<5%) it may develop into more serious conditions such as Dengue hemorrhagic fever whereby the platelet count is significantly reduced leading to bleeding tendencies and may even culminate in a more life threatening presentation i.e Dengue shock syndrome.6To understand the actual dynamics of Dengue epidemic it is important to understand the mode of its spread in affected areas. Aedes mosquito (significantly Aedes Egypti) acts a vector for this disease. Early morning and evening times7 are favoured by these mosquitos to feed on their prey. There is some evidence that the disease may be transmitted via blood products and organ donation. 8 Moreover vertical transmission (mother to child) has also been reported 9Diagnostic investigations include blood antigen detection through NS-I or nucleic acid detection via PCR. IO Cell cultures and specific serology may also be used for confirming the underlying disease. Whilst sporadic and endemic cases are part of routine medical practice and may not raise any alarm bells, outbreaks certainly need mobilization of appropriate resources for effective control. Needless to say 'prevention is better than cure' and should be the primary target of the health authorities in devising strategies for disease control.The WHO recommended 'Integrated Vector control programme', lays stress on social mobilisation and strengthening of public health bodies, coherent response of health and related departments and effective capacity building of relevant personnel and organisations as well as the community at risk. For Aedes Egypti the primary control revolves around eliminating its habitats such as open sources of water. In a local perspective in our city Peshawar, venue of the recent dengue epidemic, it may be seen in the form of incidental reservoirs such as receptacles and tyres dumped in open areas such as roof tops with rain water accumulating in them and provtdjng excellent breeding habitats, Larvicidal and insecticides may be added to more permanent sources such as watertanks and farm lands. There is not much of a role for spraying with organophosphorous agents which is at times resorted to for public consumption. Public education is the key to any effective strategy which must highlight the need for wearing clothing that fully covers the skin, avoiding unnecessary early morning and evening exposure to vector agents, application of insect repellents and use of mosquito nets. It is also important not to panic if affliction with the disease is suspected as in a vast majority of instances it is a self limiting illness without any long term harmful effects and needs simple conservative management like antipyretics and analgesics.An important consideration for responsible authorities in a dengue epidemic is to ensure that maximum management facilities for simple cases are provided at the community level through primary and secondary health care facilities and that the tertiary care hospitals are not inundated with all sort of patients demanding consultation. These later facilities should be reserved for those patients who end up with any complications or more severe manifestation of the disease.Research is underway to develop an ideal vaccine for Dengue fever. In 2016, a vaccine by the name 'Dengvaxia' was marketed in Phillipines and Indonesia. However with development of new serotypes of the virus, its efficacy has been somewhat compromised.As for treatment , there are no specific antiviral drugs. Management is symptomatic revolving mainly around oral and intravenous hydration. Paracetamol (Acetaminophen) is used for fever as compared to NSAIDS such as Ibuprophen infusion as well as blood and platelet transfusion.Data to date shows that slightly more than twenty three thousand people have been diagnosed with dengue over the past three months ie August to October there is a lower risk of bleeding with the former. Those with more severe form of the disease may need Dextran 2017, in Peshawar, Pakistan with around fourteen thousand needing admission and about sixty nine recorded deaths. The mortality is well within the acceptable international standards of less than 1% for the disease. In the backdrop of all the debate surrounding the current epidemic, one can infer that such outbreaks are best addressed with effective planningwell ahead of the time before the disease threatens to spiral out of control. Simple measures such as covering water storage facilities, using larvicidals where practical, use of insect repellents, mosquito nets and avoiding unnecessary exposure can offerthe best protection. Public health messages via print and electronic media can help educate people in affected areas and allay any anxiety building up from a fear of developing life threatening complications. Health department must mobilise all its resources to ensure local management of diagnosed patients with simple dengue fever and facilitate hospital admission only for those suffering from more severe form of the disease. Moreover the media hype into such situations needs to be addressed through constant updates and discouraging any negative politicking on the issue. To sum up Dengue fever is not really an affliction to be dreaded provided it is viewed and managed in the right perspective.

Background and Aims: Cardiac injury induces dynamic changes in the expression of microRNAs (miRs). MiR-150 is conserved between rodents and humans, and its downregulation is markedly associated with heart failure (HF) severity and outcome in humans. Using systemic and cardiomyocyte (CM)-specific knockout (KO) mouse models, we reported that miR-150 plays a cardioprotective role in part by decreasing CM apoptosis, and that pro-apoptotic small proline-rich protein 1a ( Sprr1a ) is a direct and functional target of miR-150 in CMs. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-myocardial infarction (MI), and that Sprr1a is upregulated in mouse cardiac fibroblasts (CFs) isolated from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A in MI and human CF (HCF) activation has never been established. Methods & Results: Here, we demonstrate using a novel miR-150 KO; Sprr1a -hypomorphic ( Sprr1a hypo/hypo ) mouse model that Sprr1a knockdown blunts cardiac dysfunction, damage, inflammation, apoptosis and fibrosis post-MI caused by miR-150 loss. MiR-150 KO; Sprr1a hypo/hypo mice also exhibit decreased pro-fibrotic markers in the infarct areas of hearts as compared to miR-150 KO mice. Our primary adult HCF studies further reveal that SPRR1A is upregulated in HCFs subjected to simulated ischemia/reperfusion, while its expression is downregulated in HCFs by a cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. MiR-150 knockdown in HCFs also increases pro-fibrotic SPRR1A . Lastly, protective roles of miR-150 in HCFs are in part mediated by the functional repression of SPRR1A (See Figure). Conclusions: Our findings delineate a pivotal functional interaction between miR-150 and Sprr1a as a novel regulatory mechanism pertinent to CF activation post-MI. This axis could be a therapeutic target for intervention in ischemic HF and cardiac fibrosis.

AbstractThe pulmonary and cardiovascular systems have profound effects on each other. Overall cardiac function is determined by heart rate, preload, contractility, and afterload. Changes in lung volume, intrathoracic pressure (ITP), and hypoxemia can simultaneously change all of these four hemodynamic determinants for both ventricles and can even lead to cardiovascular collapse. Intubation using sedation depresses vasomotor tone. Also, the interdependence between right and left ventricles can be affected by lung volume-induced changes in pulmonary vascular resistance and the rise in ITP. An increase in venous return due to negative ITP during spontaneous inspiration can shift the septum to the left and cause a decrease in left ventricle compliance. During positive pressure ventilation, the increase in ITP causes a decrease in venous return (preload), minimizing ventricular interdependence and will decrease left ventricle afterload augmenting cardiac output. Thus, positive pressure ventilation is beneficial in acute heart failure patients and detrimental in hypovolemic patients where it can cause a significant decrease in venous return and cardiac output. Recently, this phenomenon has been used to assess patient's volume responsiveness to fluid by measuring pulse pressure variation and stroke volume variation. Heart–lung interaction is very dynamic and changes in lung volume, ITP, and oxygen level can have various effects on the cardiovascular system depending on preexisting cardiovascular function and volume status. Heart failure and either hypo or hypervolemia predispose to greater effects of ventilation of cardiovascular function and gas exchange. This review is an overview of the basics of heart–lung interaction.

AbstractPurposeMRI‐guided adaptive radiotherapy can directly monitor the anatomical positioning of the intended target during treatment with no additional imaging dose. Elekta has recently released its comprehensive motion management (CMM) solution that enables automatic radiation beam‐gating on the Unity MR‐Linac. Easily visualized targets that are distinct from the surrounding anatomy can be used to drive automatic gating decisions from the MRI cine imaging. However, poorly visualized targets can compromise the tracking and gating capabilities and may require surrogate tracking structures. This work presents strategies to generate robust tracking surrogates for a variety of treatment sites, enabling a wider application of CMM.MethodsSurrogate tracking strategies were developed from a cohort of patients treated using the CMM system on the Unity MR‐Linac for treatment sites of the lung, pancreas, liver, and prostate. These sites posed challenging visualization or tracking of the primary target thereby compromising the tracking accuracy. Surrogate structures were developed using site‐specific strategies to improve the imaging textured detail within the tracking volume while avoiding the dynamic overwhelming hypo‐ or hyper‐intense anatomical structures. These surrogate volumes were applied within the anatomical positioning monitoring system as a proxy that drove the CMM gating decisions on the treatment unit.ResultsRobust site‐specific surrogate structures were developed. Surrogate tracking structures for centrally located thoracic targets were created by expanding the target peripherally away from the heart and great vessels and into the lung. Pancreas surrogates required a vertically expanded column intersecting with the inferior liver edge. For the liver and prostate, surrogate structures consisted of a uniform expansion of the target, with liver surrogates intersecting the proximal liver edge or diaphragm while avoiding nearby ribs.ConclusionThese surrogate strategies have enabled the gating of complex moving targets among different treatment sites at our institution.

Abstract Myocardial infarction (MI) can result in sympathetic nerve loss in the infarct region. However, the contribution of hypo-innervation to electrophysiological remodeling, independent from MI-induced ischemia and fibrosis, has not been comprehensively investigated. We present a novel mouse model of regional cardiac sympathetic hypo-innervation utilizing a targeted-toxin (dopamine beta-hydroxylase antibody conjugated to saporin, DBH-Sap), and measure resulting electrophysiological and Ca2+ handling dynamics. Five days post-surgery, sympathetic nerve density was reduced in the anterior left ventricular epicardium of DBH-Sap hearts compared to control. In Langendorff-perfused hearts, there were no differences in mean action potential duration (APD80) between groups; however, isoproterenol (ISO) significantly shortened APD80 in DBH-Sap but not control hearts, resulting in a significant increase in APD80 dispersion in the DBH-Sap group. ISO also produced spontaneous diastolic Ca2+ elevation in DBH-Sap but not control hearts. In innervated hearts, sympathetic nerve stimulation (SNS) increased heart rate to a lesser degree in DBH-Sap hearts compared to control. Additionally, SNS produced APD80 prolongation in the apex of control but not DBH-Sap hearts. These results suggest that hypo-innervated hearts have regional super-sensitivity to circulating adrenergic stimulation (ISO), while having blunted responses to SNS, providing important insight into the mechanisms of arrhythmogenesis following sympathetic nerve loss.

The arterial vasculature undergoes profound changes across the lifespan. This vascular aging manifests as structural (e.g., vascular rarefaction) and functional (e.g., endothelial dysfunction) maladaptations. These age-related maladaptations contribute to the hypo-perfusion of skeletal muscle during conditions that require an elevated blood supply and substrate delivery (e.g., exercise) by tipping the vasoactive balance in favor of vasoconstriction. Acute heat exposure increases body and tissue temperature, increases blood flow and shear stress throughout the arterial tree, and initiates a humoral response. Importantly, chronic exposure to these temperature-dependent stimuli may reverse age-related vascular dysfunction, thereby improving perfusion of active skeletal muscle (i.e., exercise hyperemia). However, the effect of chronic heat therapy on exercise hyperemia has never been explored. Therefore, the purpose of this pilot study was to test the hypothesis that home-based heat therapy would increase skeletal muscle blood flow in older adults performing plantar flexion exercise. Six older adults (5 women; 67 ± 4 years) performed graded (5, 9, and 14 kg) unilateral dynamic plantar flexion exercise before (pre) and after (post) 8 weeks of home-based heat therapy. Each session of heat therapy required participants to immerse their lower legs ~33 cm into a heated (~ 42°C) and circulated water bath 4 days per week, for 45 min per session. Dynamic plantar flexion exercise was performed using a duty cycle of 1 s contraction and 2 s relaxation. Superficial femoral artery blood velocity and diameter were measured via Duplex ultrasonography and used to calculate the change in blood flow measured from baseline to each stage of exercise. Vascular conductance was calculated as flow/pressure. The change in leg blood flow during exercise was increased following heat therapy ( P = 0.08 for main effect of time), an effect that was mediated by augmented vascular conductance (5 kg: pre, Δ143 ± 89 ml/min/mmHg vs post, Δ188 ± 89 ml/min/mmHg; 9 kg: pre, Δ225 ± 89 ml/min/mmHg vs post, Δ234 ± 89 ml/min/mmHg; 14 kg: pre, Δ264 ± 89 ml/min/mmHg vs post, Δ290 ± 89 ml/min/mmHg; P = 0.07). Our preliminary data suggest that home-based heat therapy increases skeletal muscle blood flow during exercise in older adults, and may serve as a pragmatic intervention to improve exercise and functional capacity in this population. Supported by: American Heart Association TPA958179 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiac function is highly reliant on mitochondrial oxidative metabolism and fitness. The circadian clock is critically linked to vital physiological process including mitochondrial fission, fusion and quality control mechanisms. However, little is known of how the circadian clock regulates these vital processes in the heart. Herein, we identified a putative circadian Clock - mitochondrial interactome that gates an adaptive stress response for cell viability during myocardial ischemia reperfusion (I-R) injury. We show that Clock transcriptionally coordinates expression of mitochondrial dynamic fusion and fission, bioenergetic and quality control proteins in cardiac myocytes. Transcriptome and gene ontology mapping revealed Clock defective hearts subjected to I-R exhibited major transcriptional deficits in several key survival processes including mitochondrial dynamics, bioenergetics and autophagy that were reduced further following I-R. Gain of function of Clock activity re-established gene transcription of mitochondrial respiratory complex activity, quality control mechanisms and cell viability. Collectively, our data show that mitochondrial fitness and cell survival is mutually dependent upon and obligatorily linked to transcription of the circadian Clock gene in cardiac myocytes. Our data suggest the functional loss of Clock activity predisposes cardiac myocytes to metabolic catastrophe. Hence, therapeutic strategies designed to preserve circadian clock activity in the hearts may prove beneficial in reducing morbidity and mortality following ischemia -related pathologies such as myocardial infarction.

Human heart regeneration is one of the most critical unmet clinical needs at a global level. Muscular regeneration is hampered both by the limited renewing capacity of adult cardiomyocytes and the onset of cardiac fibrosis, resulting in reduced compliance of the tissue. Pluripotent stem cell strategies have proven efficacious for heart regeneration in rodents, pigs and primates, but approaches to specifically drive cell migration to the site of injury and inhibit subsequent fibrosis have been elusive. By virtue of human cardiac progenitor lineage tracing and single-cell transcriptomics, we uncover coordinated muscular regeneration in injured non-human primate heart bio-mimics. Remuscularization occured via directed migration of human ventricular progenitors to site of injury, concomittant fibroblast repulsion targeting fibrosis, and ultimately functional replacement of damaged cardiac muscle by differentiation and electromechanical integration. Single-cell RNAseq captured distinct capabilities, such as migration towards a CXCL12 gradient and fibroblast repulsion regulated by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Injection of human cardiac progenitors into hypo-immunogenic CAG-LEA29Y transgenic porcine hearts following radiofrequency ablation injury proved their chemotactic response and ability to generate a remuscularized scar in vivo . Transplantation of ~500 million cryopreserved human embryonic stem cell-derived progenitors vs cadiomyocytes similarly enhance cardiac function in pigs with myocardial infarctions. However, the risk of graft-associated ventricular arrhythmias from ectopic pacemaker automaticity shown by electroanatomical mapping is significantly lower in progenitor- compared to cardiomyocyte-treated hearts. Moreover, progenitor grafts exhibit larger CD31 + blood vessel networks and lower CD68 + immune cell infiltration. Our study demonstrates that inherent developmental programs within cardiac progenitors are sequentially activated in the context of disease, allowing the cells to sense, counteract injury and integrate into the host environment. As such, they may represent an ideal bio-therapeutic for functional heart rejuvenation.

Abstract. This study investigated cardiovascular variability and stress reactivity in major depressive disorder (MDD). While previous research has documented reduced heart rate variability, knowledge about blood pressure variability in MDD remains scarce. Regarding reactivity, a particular focus was placed on the time courses of the cardiovascular responses, which may provide insight into the autonomic mechanisms underlying the hypo-reactivity expected in MDD. In 76 MDD patients and 71 healthy controls, blood pressure was continuously recorded at rest and during mental stress induced by a 3-min serial subtraction task. Compared to controls, patients exhibited lower systolic and diastolic blood pressure, heart rate variability, and systolic and diastolic blood pressure variability. Moreover, smaller stress-related changes in heart rate, systolic and diastolic blood pressure, and sensitivity of the cardiac baroreflex arose in patients. Cardiovascular parameters did not differ between patients using antidepressants and unmedicated patients. According to time-course analysis, reduced hemodynamic modulations in MDD mainly occurred after 50 s of the stress period. Low heart rate variability in MDD reflects deficient top-down integration of the brain mechanisms allowing flexible autonomic and behavioral control; diminished blood pressure variability is indicative of poor homeostatic capacity with respect to the regulation of blood pressure and organ perfusion. Moreover, blunted cardiovascular reactivity implies poor adjustment of energetic resources to internal and environmental demands and may be a correlate of deficient motivational dynamics characterizing MDD. While cardiovascular hypo-reactivity in MDD may be mediated by baroreflex and adrenergic mechanisms, the fast-acting parasympathetic system may play a subordinate role.

Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular degenerative disorder that leads to premature death in the teens because of multiple dysfunctions in the heart and skeletal muscle. DMD is caused by the absence of dystrophin, a sarcolemma protein encoded by the dmd gene, located on the X chromosome. 1:5,000 boys are diagnosed with DMD annually, and there is no cure. Clinically, steroid-based treatments reduce inflammation and thus, palliate skeletal muscle pathology. With improvements in the skeletal muscle, DMD-associated cardiomyopathy has become the leading cause of mortality because nearly all patients develop cardiac disease by age 20. Connexin 43 (Cx43) is a gap junction protein and is responsible for the electrical propagation of signals in the heart; it is upregulated and undergoes pathological remodeling, away from the intercalated disc in the heart of DMD mice (mdx) and patients. Hypo-phosphorylation of a specific triplet of serines in Cx43 had been found in mdx and DMD hearts. To study a potential rescue role for Cx43 phosphorylation in DMD, the triplet of serine residues was replaced by glutamic acid or alanine residues to create a phospho-mimic (Cx43-S3E) or a phospho-dead (Cx43-S3A) version of Cx43 respectively. We found that Cx43-S3E but not Cx43-S3A prevents Cx43 remodeling and development of fibrotic cardiomyopathy, arrhythmias, and heart failure in mdx mice. Remarkably, inhibition of hyperdensified, dystrophic microtubule (MT) polymerization by treatment with colchicine (Colch) enhances Cx43 phosphorylation and reduces Cx43 remodeling in dystrophic hearts, suggesting the presence of a MT-Cx43 regulatory connection. This connection could play an important role in the development of dystrophic cardiomyopathy. Our studies explore the electrophysiological properties of Cx43-S3E in DMD cardiomyocytes, and investigate a requirement for Cx43-S3A in the Colch-dependent improvement of the MT dynamics, uncovering a novel link between phospho-Cx43 and MT organization. Furthermore, the results suggest a novel target for the treatment of DMD-cardiomyopathy.

Introduction-aim and scope: This article highlights a rare observation in 2 patients admitted to the hospital who were evaluated with simultaneous EEG and EKG monitoring due to having episodic clinical spells suspected as being consistent with seizure activity. What however was noted were episodes of asystole causing syncope and brain wave activity persisted for approximately 24 seconds with other clinical features noted in the case histories including an incipient actual seizure in one case. We believe that these patients were fortunate to have such diagnosis made as risks of sudden cardiac death with asystole are high and may be associated with catastrophic neurologic injury and outcomes, and these patients were able to be referred for subsequent cardiac electrophysiologic evaluation and further management1-4. Rationale: This report highlights 2 clinical patients with asystole while being monitored with Video EEG (Electroencephalogram) with EKG (Electrocardiogram) that have a complete dataset available for study. One patient exhibited clinical symptoms of syncope and hypoperfusion and one patient after asystole exhibited subsequent electrographic seizure activity. This article descriptively and retrospectively reviews these rarely noted cases and the clinicopathologic details. Methods: In a hospital system with currently a level 4 epilepsy center that is a member of the US NAEC-National Association of Epilepsy Centers, two patients with asystole were identified as above. This publication provides a retrospective descriptive analysis of two cases that had a complete clinical data set. Results: Asystole is associated with clinical cerebral hypo perfusion in one case, and in another case, hypo perfusion with the EEG features of hypo perfusion similar to the first case however such is followed by actual electrographic seizure activity. We postulate that these findings may be rarely-recorded manifestations during asystole and deserve further study. Successful clinical management of these cases along with the EEG manifestations are described in the article. Electrocerebral rhythms in both cases persist for approximately 24 seconds after asystole although the exact delineation of the cerebral flow dynamics are not completely understood in this retrospective observational study. Conclusions: The cases delineate that the pathophysiology and the concomitant use of EEG and EKG monitoring with video during asystole deserve further study as clinical manifestations may not be identified otherwise without such recordings. Monitoring patients with simultaneous Video EEG and EKG recordings may be necessary for optimal diagnostic assessment and therapeutic outcome where clinical decision making by multidisciplinary subspecialty care teams can ensue in real time as noted in this article.

Missense mutations in alpha-tropomyosin (TPM1) can lead to development of hypertrophic (HCM) or dilated cardiomyopathy (DCM). HCM mutation E62Q and DCM mutation E54K have previously been studied extensively in experimental systems ranging from in vitro biochemical assays to animal models, although some conflicting results have been found. We undertook a detailed multi-scale assessment of these mutants that included atomistic simulations, regulated in vitro motility (IVM) assays, and finally physiologically relevant human engineered heart tissues. In IVM assays, E62Q previously has shown increased Calcium sensitivity. New molecular dynamics data shows mutation-induced changes to tropomyosin dynamics and interactions with actin and troponin. Human engineered heart tissues (EHT) were generated by seeding iPSC-derived cardiomyocytes engineered using CRISPR/CAS9 to express either E62Q or E54K cardiomyopathy mutations. After two weeks in culture, E62Q EHTs showed a drastically hypercontractile twitch force and significantly increased stiffness while displaying little difference in twitch kinetics compared to wild-type isogenic control EHTs. On the other hand, E54K EHTs displayed hypocontractile isometric twitch force with faster kinetics, impaired length-dependent activation and lowered stiffness. Given these contractile abnormalities, we hypothesized that small molecule myosin modulators to appropriately activate or inhibit myosin activity would restore E54K or E62Q EHTs to normal behavior. Accordingly, E62Q EHTs were treated with 0.5μM mavacamten (to remedy hypercontractility) and E54K EHTs with 0.5 μM danicamtiv (to remedy hypocontractility) for 4 days, followed by a 1 day washout period. Upon contractility testing, it was observed that the drugs were able to reverse contractile phenotypes observed in mutant EHTs and restore contractile properties to levels resembling those of the untreated wild type group. The computational, IVM and EHT studies provide clear evidence in support of the hyper- vs. hypo-contractility paradigm as a common axis that distinguishes HCM and DCM TPM1 mutations. Myosin modulators that directly compensate for underlying myofilament aberrations show promising efficacy in human in vitro systems.

The intrinsic capacity of the heart to regenerate and replace damaged myocardium by promoting cardiac stem cell differentiation is one of the key repair mechanisms following acute injury to heart. Mitochondrial dysfunction plays an important role in various heart disorders including myocardial infarction. Micro RNAs are implicated in pathogenesis of various cardiac diseases. Cardiac specific miR-499 was shown to regulate mitochondrial fission by inhibiting Drp-1 (Dynamin-related protein). We hypothesize that mitochondrial division inhibitor (Mdivi-1) ameliorates adverse post myocardial infarction remodeling by increasing the expression of miR-499 thereby promoting the ventricular cardiac stem cell differentiation . To verify this, we created myocardial infarction in wild type (C57BL6/J) animals and treated them with Mdivi-1(50mg/kg BW) for 4 weeks. Cardiac function was assessed by echocardiography and pressure volume loop. Individual micro RNA assay was performed to compare miR-499 expression among the groups. Endogenous cardiac stem cell expression was assessed by C-kit marker. Our results showed that Mdivi-1 promotes miR-499 expression and cardiac stem cell differentiation. Echo data revealed improved ejection fraction and left ventricular function. Based on these findings we conclude that Mdivi-1 ameliorates adverse post myocardial infarction remodeling by promoting miR-499 expression and cardiac stem cell differentiation.

Cardiovascular deconditioning, cephalad fluid shifts, and altered sympathetic activity in weightlessness may elicit changes in vascular structure and function akin to vascular ageing. Head-down tilt bedrest is an established terrestrial model for weightlessness and elicits similar cardiovascular responses. We hypothesized that 30 days head-down tilt bedrest (HDTBR) worsens flow mediated dilation (FMD), a non-invasive endothelial function marker, and that daily orthostatic stimuli or physical exercise attenuates the response. Fourty-seven healthy individuals (20 women, age 35±9 years, BMI 23.7±2.6 kg/m 2 ) were assigned to 30 days of strict HDTBR and divided into four groups: Daily 6 hours of upright sitting (positive control, n=11); 6 hours of -25 mmHg lower body negative pressure (n=12); 60 minutes of supine cycling followed by 6 hours of thigh cuff venous occlusion 6 days per week (n=12), or no countermeasure (negative control, n=12). We measured upper arm blood pressure and heart rate 5 days before and immediately after bedrest. We assessed plasma volume by carbon monoxide-rebreathing 2 days before and on day 28 of bedrest. We determined FMD of the brachial artery 5 days before, on day 28 of bedrest, and after 13-day recovery. We collected blood samples to measure pro- and anti-inflammatory cytokines. Heart rate was elevated after bedrest (p<0.0001) but remained constant in seated and cycling groups (seated MD 5±2 /min, cycling MD 5±2, p=0.0051). Systolic blood pressure increased in all groups (MD 4±1 mmHg, p=0.0004). Diastolic blood pressure was higher post-bedrest in the control group (MD 8±2 mmHg, p=0.0002) but remained constant in the countermeasure groups. Plasma volume was reduced after bed rest (MD -400±37 ml, p<0.0001) but maintained in the cycling group (MD 147±72 ml, p=0.0001). FMD did not differ between groups, but was higher at bedrest (MD 1.9±0.8 %, p=0.0481), whereas recovery values did not differ from baseline. Resting brachial artery diameter tended to be higher at bedrest (p=0.0876). Cytokines revealed no clinically relevant inflammatory response. Head-down tilt bedrest-induced cardiovascular deconditioning, which was not completely abolished by any countermeasure, paradoxically increased flow-mediated brachial vasodilation. Additional cardiovascular risk factors may be required to express endothelial dysfunction in the face of reduced physical activity.

The role of Drp1-mediated mitochondrial fission in normal hearts is controversial. Cardiomyocyte mitochondria are hypo-dynamic, but mitochondrial dynamism factors are abundantly expressed. Cardiac-specific Drp1 gene deletion (KO) provokes mitochondrial enlargement, MPTP-dependent cardiomyocyte loss, and dilated cardiomyopathy (Song et al Cell Metab, 2015). We postulated that Drp1-dependent mitochondrial fission is essential for triage and elimination of damaged cardiomyocyte mitochondria by Parkin-mediated mitophagy. Others described no benefit of Parkin KO in mice with perinatal cardiac Drp1 KO (Kageyama et al EMBO J, 2014), but these Parkin KO mice have little basal phenotype due to germ-line compensation. Here, we assessed the individual and interactive roles of Parkin and Drp1 in adult mouse hearts by conditionally ablating each gene (Cre-Lox at 8 wks), separately and in combination. Parkin KO hearts appeared normal; as reported, Drp1 KO caused lethal cardiomyopathy after 6-7 wks. Cardiac-specific Parkin KO concomitant with Drp1 KO ameliorated the underlying cardiomyopathy by: 1. Increasing survival (94% vs 56%; P<0.0001); 2. Enhancing cardiac contractility (LV FS 36.2±4.0 vs 23.2±1.7%; P=0.01); 3. Decreasing adverse remodeling (LV r/h 5.0±0.5 vs 6.3±0.4; P=0.05); 4. Reducing cardiomyocyte necrosis (1.9±0.5 vs 5.0±1.2%; P=0.05) and replacement fibrosis (33.3±5.3 vs 13.0±1.5%; P=0.02); 5. Attenuating mitochondrial deficiency (5.7±0.4 vs 4.7±0.6 μg/mg; P=0.20). Deleting Parkin did not affect mitochondrial enlargement or respiratory function in Drp1 KO cardiomyocytes, but normalized mitochondrial-associated LC3 and p62, mitophagy markers increased in cardiac Drp1 KO. These studies show how Drp1-mediated mitochondrial fission and Parkin-mediated mitophagy interact to maintain the quality of cardiac mitochondria: Interrupting mitochondrial fission (Drp1 KO) prevents segregation of damaged mitochondrial components into daughter organelles normally targeted for mitophagy; mitophagy thus ultimately consumes fission-defective parent organelles. Parkin KO suppresses generalized mitophagy, postponing (but not preventing) the Drp1 KO cardiomyopathy.

Introduction: Hypertension is the most common chronic cardiovascular disease, being multifactorial in origin and an important cause of morbidity and mortality worldwide. Complex behaviors of heart rate series have been widely recognized and the loss of complexity in heart rate variability (HRV) has been shown to predict adverse cardiovascular outcomes. We hypothesized that two-kidney one clip (2K1C) hypertension reduces the HRV complexity in mice. Methods and Results: C57BL/6 mice were anesthetized with isoflurane and submitted to 2K1C hypertension by placing a silver clip (0.12 mm) around left renal artery. After 4 weeks, mice were implanted with subcutaneous electrocardiogram (ECG) electrodes and allowed to recover for 48 h. On the day of the experiment, the ECG was recorded for 30 minutes in conscious, unrestrained mice. At the end of the recording, arterial pressure (AP) was directly measured in each mouse under isoflurane anesthesia. RR interval time series were generated and the complexity of HRV was determined using detrending fluctuation analysis (DFA) and multiscale entropy (MSE). Mean AP was higher in 2K1C mice (133±2 vs 93±4 mmHg) while the HR was similar between groups. DFA scaling exponents were calculated in short (5 to 15), mid (30 to 200) and long (200 to 1500) window sizes, but only the long-term exponent was different between groups (1.27±0.09 vs 0.89±0.08 in 2K1C and sham mice, respectively). MSE was calculated up to scale 20 and averaged in short (1 to 5) and long (6 to 20) time scales. In both short (0.75±0.16 vs 1.25±0.11) and long (0.76±0.17 vs 1.22±0.09) ranges, entropy is lower in hypertensive mice. Conclusions: The complexity of HRV dynamics was found lower in renovascular hypertensive mice. Both sympathetic and vagal control of the heart seems to be involved in this process, as predictability (MSE) and fractality (DFA) is affected in various temporal scales. Nevertheless, the greatest entropy difference between groups is found at scale 6, which is closely related to respiration.

Mechanical loading (e.g. blood pressure) is a critical component of heart disease. Here, we developed a simple, scalable iPSC-derived micro heart muscle (μHM) model by grafting μHM on elastomeric substrates with different stiffnesses to simulate afterload. For tissue traction force microscopy (TFM), substrates were fabricated by spin coating a PDMS base layer followed by spin coating an ultra-thin PDMS/fluorescent bead (1-micron) layer. Substrates were then covalently grafted with fibronectin via glutaraldehyde. Sylgard 184 ‘dog-bone’ shaped stencils were added onto substrates to control tissue geometry. Both isogenic control (WTC) and PKP2 -/- iPSC with GCaMP6f calcium indicator were differentiated using small molecule Wnt pathway modulators and were then purified (81±15% TNNT2 positive) for making tissue. Contractility was quantified using open source TFM software and calcium dynamics were measured using GCaMP6f intensity. At day 9, we observed a significant increase in contractility of isogenic control iPSC-μHM on stiffer substrates, the average traction from tissues formed on 5kPa, 15kPa and 30kPa substrates are 19.7μN, 28.7 μN and 36.7 μN. However, PKP2 -/- iPSC-μHM showed a non-significant traction force increase from 5kPa (23.6 μN) to 15kPa (26.9 μN) although prolonged calcium transients were found on stiffer substrates for both WTC and PKP2 -/- μHM, which may indicate calcium-contraction uncoupling of the PKP2 -/- μHM. Immunostaining shows a slightly increase in cell size towards stiffer substrates. These data suggest that mechanical load (e.g. afterload) may be necessary to reveal genotype-phenotype relationships within in vitro iPSC-based models.

Abstract Study Objectives We aimed to characterize the cerebral hemodynamic response to obstructive sleep apnea/hypopnea events, and evaluate their association to polysomnographic parameters. The characterization of the cerebral hemodynamics in obstructive sleep apnea (OSA) may add complementary information to further the understanding of the severity of the syndrome beyond the conventional polysomnography. Methods Severe OSA patients were studied during night sleep while monitored by polysomnography. Transcranial, bed-side diffuse correlation spectroscopy (DCS) and frequency-domain near-infrared diffuse correlation spectroscopy (NIRS-DOS) were used to follow microvascular cerebral hemodynamics in the frontal lobes of the cerebral cortex. Changes in cerebral blood flow (CBF), total hemoglobin concentration (THC), and cerebral blood oxygen saturation (StO2) were analyzed. Results We considered 3283 obstructive apnea/hypopnea events from sixteen OSA patients (Age (median, interquartile range) 57 (52-64.5); females 25%; AHI (apnea-hypopnea index) 84.4 (76.1-93.7)). A biphasic response (maximum/minimum followed by a minimum/maximum) was observed for each cerebral hemodynamic variable (CBF, THC, StO2), heart rate and peripheral arterial oxygen saturation (SpO2). Changes of the StO2 followed the dynamics of the SpO2, and were out of phase from the THC and CBF. Longer events were associated with larger CBF changes, faster responses and slower recoveries. Moreover, the extrema of the response to obstructive hypopneas were lower compared to apneas (p < .001). Conclusions Obstructive apneas/hypopneas cause profound, periodic changes in cerebral hemodynamics, including periods of hyper- and hypo-perfusion and intermittent cerebral hypoxia. The duration of the events is a strong determinant of the cerebral hemodynamic response, which is more pronounced in apnea than hypopnea events.

The purpose of this study was to compare the cardiovascular autonomic effects between dynamic aerobic, resistance and combined exercise training in ovariectomized diabetic female rats. Female Wistar rats (200-220g) were divided into 4 ovariectomized (bilateral ovaries removal) diabetic (streptozotocin, 50mg/kg, iv) groups: sedentary (DOS) and trained by an aerobic protocol on a treadmill (DOTA), by a resistance protocol in ladder (DOTR), or by a combined protocol in ladder+treadmill on alternate days (DOTC). After 8 weeks of training, the animals were cannulated to arterial pressure (AP) recording and baroreflex sensitivity (BS) evaluation. Heart rate (HR) and systolic AP variabilities were analyzed in the time and frequency domains. Exercise training induced an increase of 77% in the run capacity in the DOTA group (DOS: 8.6±0.6; DOTA: 15.3±0.4; DOTR: 11.5±1.6; DOTC: 15.0±0.2 min), 60% in the maximum load in DOTR group (DOS: 179.7±11.0; DOTA: 167.3±1.5; DOTR: 288.4±7.5; DOTC: 284.6±10.2 % of body weight), and increases in both exercise tests in DOTC (75% and 58%, respectively). All trained animals showed normalization of diabetic induced-resting hypotension and bradycardia, associated with increased HR variance (DOS: 39.6±2.6; DOTA: 71.2±7.2; DOTR: 70.9±12.1; DOTC: 65.7±6.1 ms2) and normalization of the LF band of pulse interval (DOS: 2.7±0.3; DOTA: 5.3±0.4; DOTR: 7.2±1.5; DOTC: 6.8±0.8 ms2) (vs. DOS). The DOTA and DOTC groups (but not DOTR) had higher BS (tachycardic and bradycardic responses), and attenuation in SAP variability (DOS: 7.4±0.8; DOTA: 12.7±1.1; DOTR: 8.9±1.0; DOTC: 13.3±1.0 mmHg2) in relation to DOS. Mortality was higher in DOS group when compared to trained group. In conclusion, the results showed that dynamic aerobic, resistance or combined exercise training induced benefits in physical capacity, hemodynamic and autonomic parameters after ovarian hormone deprivation in diabetic rats. However, the combined exercise training promoted additional effects than aerobic or resistance training in this condition.

Introduction: Corin is a cardiac membrane protease that activates pro-ANP and pro-BNP. Changes in circulating corin levels have been linked to poor clinical outcomes following acute myocardial infarction (AMI) in some, but not all studies and the pathophysiologic mechanisms responsible for these changes are not understood. Hypothesis: We examined the hypothesis that plasma corin levels are closely correlated with alterations in cardiac corin expression related to acute ischemic injury. Methods: AMI was induced by left anterior descending coronary artery ligation. Hearts and plasma were assessed at 3 hrs, 24 hrs and 3 days post AMI. We measured plasma corin, troponin T levels, cardiac corin, infarct size, ANP and BNP expression by ELISA, qRT-PCR and histology staining. Cardiac function was assessed by echocardiography. Data represent means ± SE of n = 7-9 mice per group. Results: Plasma corin levels were significantly increased at 3 hrs (1090±237.50 pg/ml, P<0.05), 24 hrs (1666±214.50 pg/ml, P<0.001), and 3 days (1221±185.90 pg/ml, P<0.01P<0.01) post-AMI with a “rise-and-fall” pattern similar as troponin T when compared to non-MI group (553.9±96.13 pg/ml). In contrast, at the same time-points, cardiac corin expression dropped by 5% (P>0.05), 69% (P<0.001) and 65% (P<0.001) as measured by real time PCR and 30% (P<0.05), 76% (P<0.001) and 75% (P<0.001) by immunohistology. Transcript levels of pro-ANP increased at 24 hrs (20%) and 3 days (3.8-fold, P<0.001) vs. non-MI mice. Transcript levels of pro-BNP also increased 3.2-fold at 24 hrs (P<0.001) and 1.8-fold at 3 days (P<0.01) post MI. EF% and FS% consistently dropped by 36% (P<0.01), 60% (P<0.001) and 68% (P<0.001) and 42% (P<0.01), 63% (P<0.001) and 72% (P<0.001) respectively. Plasma corin levels were negatively correlated with cardiac corin (P<0.01), EF% and FS% (P<0.05) and positively correlated with infarct sizes (P<0.01). Conclusions: Plasma corin levels markedly increase and then decline following AMI, reflecting dynamic changes of cardiac corin expression related to acute cardiomyocyte injury. As such, plasma corin levels may serve as a valuable marker to indicate the severity of acute myocardial injury and, over a longer term, expression by the remaining viable cardiomyocyte mass.

INTRODUCTION: Increased aortic stiffness is correlated with many clinically adverse cardiovascular outcomes. The “gold standard” quantitative index for arterial stiffness is the pulse wave velocity (PWV). We have developed a new method called the Intrinsic Frequency ( IF ), which views the arterial pressure waveform as a piecewise combination of two coupled systems, the heart and arterial system which are decoupled upon closure of the aortic valve. Each of these dynamical systems has an inherent frequency of operation (ω 1 and ω 2 ) which gives information about LV function (ω 1 ) as well as arterial dynamics (ω 2 ). METHODS: IF methodology is based on Sparse Time-Frequency Representation method. It uses an effective L 2 -minimization to extract the second intrinsic frequency (ω 2 ) from an aortic pressure waveform. To examine the clinical relevance of this method, IF was applied to aortic pressure waveforms taken from published works. These aortic waveforms were selected from a healthy population free of any cardiovascular diseases (CVD). RESULTS: Our results show that ω 2 represents information about the arterial system and that these measurements are highly correlated with PWV ( r=0.9 ). CONCLUSION: These results show ω 2 can potentially be used to evaluate aortic rigidity and calculate aortic PWV from one pressure waveform. Increased aortic rigidity is a common feature in normal aging and is accelerated in many CVDs including diabetes. One unique advantage of the method is that only a single measurement of the pressure waveform is required to extract the result. Therefore, ω 2 may be employed as a clinically effective noninvasive assessment of cardiovascular health.

The renin-angiotensin system (RAS) plays key roles in the regulation of blood pressure and body fluid dynamics. It is now recognized that a wide variety of tissues and organs, including the heart, vasculature, kidney and nervous system, among others, contain a local tissue RAS, which exerts autocrine/paracrine effects and acts independently of the systemic RAS. In 2006, we isolated and characterized proangiotensin-12, a component of the tissue RAS in rat small intestine. Similar angiotensin-related peptides had never been reported in humans. When we screened human urine gel filtration fractions for bioactive peptides using an antibody raised against the N-terminal portion of Angiotensin II (Ang II), we found a highly immunoreactive peptide with an apparent molecular weight of about 5,000. Therefore, we purified this peptide from 5.5 L of human urine using ion-exchange, gel-filtration, and affinity chromatography, and finally reverse-phase high-performance liquid chromatography (RP-HPLC) steps. We isolated and identified a novel Aogen-derived peptide, Big angiotensin-25 (Bang-25), which is composed of 25 amino acids and is N-glycosylated on its 14th amino acid (Asn) and has a cysteine linked to its 18th amino acid (Cys). We then assessed the distribution of Bang-25 in tissues by immunostaining with an antiserum raised against the C-terminal portion of the peptide. We found that Bang-25 was abundantly expressed in a number of human tissues, including kidney, heart, adrenal gland, pancreas and placenta. In the kidney, Bang-25 is localized predominantly to podocytes. Then, compared with angiotensinogen, Bang-25 is rapidly cleaved by chymase to Ang II, but is resistant to cleavage by renin. In the present study, we have isolated and identified a novel Angiotensin-derived peptide, Bang-25, which is composed of 25 amino acids and is N-glycosylated on its 14th amino acid (Asn) and has a cysteine linked to its 18th amino acid (Cys). The identification of Bang-25 suggests the existence of a RAS processing cascade different from the renin-catalyzed cleavage of Angiotensin to Ang I, and provides a potential target for assessing tissue RAS status and for the development of new therapeutic approaches to related diseases.

Introduction: Previous studies demonstrated that heat failure with preserved ejection fraction (HFpEF) is characterized by abnormal arterial function and left ventricle (LV)-arterial coupling. Aortic characteristic impedance (Zc) and total arterial compliance (TAC) are well-established biomarkers for quantification of the arterial function. However, the routine clinical use of these biomarkers requires both pressure and flow measurements. Intrinsic Frequency (IF) method is a novel system-based mathematical approach for the analysis of the cardiovascular dynamics that can predict HF events (Cooper et al. Hypertension, 2021 PMID: 33390053). We hypothesized that a hybrid IF-machine learning (ML) approach can compute TAC and Zc from a noninvasive carotid waveform. Method: We used data from the Framingham Heart Study (FHS) (n=6168). The reference values of Zc and TAC were computed from carotid pressure and aortic flow waveforms. IF parameters of carotid pressure waveform were used in a fully connected feed-forward neural network model. The model was trained/validated/tested on 80% of randomly selected data from all FHS data. The final model was tested on the remaining 20% of the data blinded to all stages of ML development. Result: In blind test set data, our IF-ML models showed correlations of r=0.89 and r=0.79 with the reference value of TAC and Zc, respectively (Fig 1). More importantly, the TAC and Zc from our IF-ML models showed strong correlations among HFpEF patients (r=0.9 and r=0.77 respectively) (Fig.1) Conclusion: Since IFs can be measured noninvasively (e.g. an iPhone), this method can be used to facilitate routine and noninvasive evaluation of TAC and Zc in HFpEF.

Background: Postural orthostatic tachycardia syndrome (POTS) is a common complication in Long-COVID. Long-COVID POTS (LCP) is characterized by abnormal orthostatic tachycardia, symptoms of orthostatic intolerance, and persistent inflammation. Hypothesis: Novel parameters of immune activation exist in and likely contribute to the pathogenesis of LCP. Methods: We enrolled 15 LCP patients and 5 subjects who recovered from COVID-19 infection without lingering effects as controls. Hemodynamic parameters were measured at baseline and during a 10-minute 75° head-up tilt. Flow cytometry was used to detect circulating T cells, monocyte subsets, and their cytokines. Immune synapse formation between T cells and monocytes was detected using Forster Resonance Energy Transfer (FRET) between T cell receptors (TCR) and human leukocyte antigens (HLAs). Intracellular staining was used to detect the cytokines IL-17A, IFN-γ and IL-6. Results: Subjects with LCP exhibited a greater increase in heart rate (HR) during 10-min upright tilt compared with controls (50.23± 4.6 vs. 20.33 ± 3.17 bpm, p<0.01, Figure). Circulating monocyte/T cell complexes were increased in LCP vs controls and these exhibited high TCR/HLA FRET ( p<0.005 ), suggesting immune synapse formation. Importantly, complexed T cells demonstrated higher levels of IL-17A and IFN-γ, compared to non-complexed T cells and a profound increase in intracellular IL-6 compared to non-complexed monocytes ( p<0.005 ). Notably, the percent of IFN-γ + and IL-17A + T cells in the monocyte/T cell complexes of LCP subjects positively correlated with their increase in HR (ΔHR) in 10 min active standing test (Figure). Conclusion: Circulating T cell-monocyte complexes are markedly increased in humans with LPC, and exhibit evidence of functional and dynamic cellular interactions. We propose that these contribute to persistent inflammation and the pathogenesis of autonomic dysfunction in these subjects.

The Ca2+-calmodulin dependent protein kinase II (CaMKII) plays a prime role in the development of cardiovascular diseases including heart failure and diabetes-associated vasculopathies. The multifunctional kinase can promote the genesis or sustainment of cardiovascular pathological conditions. Although the role of cardiac CaMKII is well established, literature on endothelial CaMKII is only emerging. Recent studies showed that CaMKII activation could alter expression and activity of enzymes such as eNOS suggesting that CaMKII might be involved in endothelial dysfunction. A better understanding of CaMKII signalling will lead to the improvement of cardiovascular therapies. CaMKII act as a Ca2+ sensor by its ability to decode oscillatory Ca2+ signalling through complex autophosphorylation steps. Such oscillatory Ca2+ signalling has only recently been reported in endothelium, the Ca2+ pulsars. The Ca2+ pulsars might represent a novel and distinctive activation mechanism for endothelial CaMKII. This study is aimed to elucidate the correlation between endothelial Ca2+ dynamics and CaMKII activity in microvasculature. PCR experiments showed that all four mammalian CaMKII isoforms are expressed in small murine mesenteric arteries but only variant 1 of CaMKIIβ have been identified. However, confocal microscopy revealed that only CaMKIIα, β and δ can be found in endothelial cells and only δ and γ in vascular myocytes. Moreover, α and β specifically converged at Ca2+ pulsar sites and stimulation of Ca2+ pulsars increased CaMKII clustering. Activated CaMKII (T286) also showed similar distribution. These evidences suggest that Ca2+ pulsars activate CaMKII. Our results showed that spontaneous Ca2+ pulsars are increased (54%) in arterial hypertension (AH) and can stimulate basal CaMKII activity. Indeed, CaMKII clustering is increased in AH (2 fold). However, an inverse correlation between CaMKIIβ expression and blood pressure was established (r2=0.6760), suggesting that blood pressure significantly alters expression of the kinase. This study demonstrates that CaMKII activity and expression is significantly modulated in hypertension and provides evidences that CaMKII represent an interesting therapeutic approach for vascular pathologies.

Introduction: Lack of actionable blood pressure (BP) measurements, therapeutic inertia, and suboptimal patient self-management are three key barriers to better BP control. To help address these barriers, the American Medical Association developed the Measure Accurately, Act Rapidly, and Partner with Patients Hypertension (MAP TM HTN) quality improvement program. Methods: To estimate the 10-year health and economic outcomes achieved when healthcare delivery systems adopt MAP HTN, HealthPartners Institute's ModelHealth™: Cardiovascular disease (CVD) microsimulation model was applied to conduct “what if” analyses for adopting MAP HTN nationwide and in care delivery systems of varying size. MAP HTN targets patients aged 18 to 85 years with diagnosed hypertension. To account for newly diagnosed hypertensive patients over time and outcomes that follow exposure to the program after age 85, the simulation model predicted outcomes for a dynamic cross-section of U.S. adults aged 18 to 100 years. This study was conducted from the health care sector perspective, including that of the payers for medical services and the health care delivery system that provides these services. Risk equations to predict the incidence of CVD events were derived from Framingham Heart Study data and are based upon the following risk factors: age, sex, body mass index, systolic BP (SBP), lipid levels, smoking status, diabetes status, and CVD history. Modeled outcomes over 10 years included prevalence of SBP ≥140 mmHg; incidence of cardiovascular disease (CVD) events and CVD-related mortality; averted medical costs in 2021 U.S. dollars; and net costs. Results: Nationwide adoption of MAP HTN was predicted to improve mean BP control by 4.3% and prevent 601000 CVD events, with 85000 fewer myocardial infarctions, 164000 fewer strokes and 120000 fewer CVD deaths over 10 years as compared to usual care. The majority (93%) of the estimated $17.9 billion in averted costs were among Medicare beneficiaries. Total costs of implementing MAP HTN was $12.6 billion, resulting in a predicted $5.3 billion in net savings to the health care sector over 10 years. Small and large care delivery organizations could economically benefit from implementing MAP HTN at varying levels (5-50%) of shared cost savings from payers. Conclusions: The model demonstrates that AMA’s MAP HTN has the potential to improve population health and provide a positive business case by averting future myocardial infarctions, strokes, and CVD deaths.

Introduction In this article, I explore the phenomenon of augmentation by questioning its representational nature and analyzing aesthetic modes of our interrelationship with the environment. How can senses be augmented and how do they serve as mechanisms of enhancing the feeling of presence? Media art practices offer particularly valuable scenarios of activating such mechanisms, as the employment of digital technology allows them to operate on a more subtle level of perception. Given that these practices are continuously evolving, this analysis cannot claim to be a comprehensive one, but rather aims to introduce aspects of the specific relations between augmentation, sense of proprioception, technology, and art. Proprioception is one of the least detectable and trackable human senses because it involves our intuitive sense of positionality, which suggests a subtle equilibrium between a center (our individual bodies) and the periphery (our immediate environments). Yet, as any sense, proprioception implies a communicational chain, a network of signals traveling and exchanging information within the body-mind complex. The technological augmentation of this dynamic process produces an interference in our understanding of the structure and elements, the information sent/received. One way to understand the operations of the senses is to think about them as images that the mind creates for itself. Artistic intervention (usually) builds upon exactly this logic: representation of images generated in mind, supplementing or even supplanting the existing collection of inner images with new, created ones. Yet, in case of proprioception the only means to interfere with and augment these inner images is on bodily level. Hence, the question of communication through images (or representations) should be extended towards a more complex theory of embodied perception. Drawing on phenomenology, cognitive science, and techno-cultural studies, I focus on the potential of biofeedback technologies to challenge and transform our self-perception by conditioning new pathways of apprehension (sometimes by creating mechanisms of direct stimulation of neural activity). I am particularly interested in how the awareness of the self (grounded in the felt relationality of our body parts) is most significantly activated at the moments of disturbance of balance, in situations of perplexity and disorientation. Projects by Marco Donnarumma, Sean Montgomery, and other artists working with biofeedback aesthetically validate and instantiate current research about neuro-plasticity, with technologically mediated sensory augmentation as one catalyst of this process. Augmentation as Representation: Proprioception and Proprioceptive Media Representation has been one of the key ways to comprehend reality. But representation also constitutes a spatial relation of distancing and separation: the spectator encounters an object placed in front of him, external to him. Thus, representation is associated more with an analytical, rather than synthetic, methodology because it implies detachment and division into parts. Both methods involve relation, yet in the case of representation there is a more distinct element of distance between the representing subject and represented object. Representation is always a form of augmentation: it extends our abilities to see the "other", otherwise invisible sides and qualities of the objects of reality. Representation is key to both science and art, yet in case of the latter, what is represented is not a (claimed) "objective" scheme of reality, but rather images of the imaginary, inner reality (even figurative painting always presents a particular optical and psychological perspective, to say nothing about forms of abstract art). There are certain kinds of art (visual arts, music, dance, etc.) that deal with different senses and thus, build their specific representational structures. Proprioception is one of the senses that occupies relatively marginal position in artistic production (which is exactly because of the specificity of its representational nature and because it does not create a sense of an external object. The term "proprioception" comes from Latin propius, or "one's own", "individual", and capio, cepi – "to receive", "to perceive". It implies a sense of one's self felt as a relational unity of parts of the body most vividly discovered in movement and in effort employed in it. The loss of proprioception usually means loss of bodily orientation and a feeling of one's body (Sacks 43-54). On the other hand, in case of additional stimulation and training of this sense (not only via classical cyber-devices, like cyber-helmets, gloves, etc. that set a different optics, but also techniques of different kinds of altered states of mind, e.g. through psychotropics, but also through architecture of virtual space and acoustics) a sense of disorientation that appears at first changes towards some analogue of reactions of enthusiasm, excitement discovery, and emotion of approaching new horizons. What changes is not only perception of external reality, but a sense of one's self: the self is felt as fluid, flexible, with penetrable borders. Proprioception implies initial co-existence of the inner and outer space on the basis of originary difference and individuality/specificity of the occupied position. Yet, because they are related, the "external" and "other" already feels as "one's own", and this is exactly what causes the sense of presence. Among the many possible connections that the body, in its sense of proprioception, is always already ready for, only a certain amount gets activated. The result of proprioception is a special kind of meta-stable internal image. This image may not coincide with the optical, auditory, or haptic image. According to Brian Massumi, proprioception translates the exertions and ease of the body's encounters with objects into a muscular memory of relationality. This is the cumulative memory of skill, habit, posture. At the same time as proprioception folds tactility in, it draws out the subject's reactions to the qualities of the objects it perceives through all five senses, bringing them into the motor realm of externalizable response. (59) This internal image is not mediated by anything, though it depends directly on the relations between the parts. It cannot be grasped because it is by definition fluid and dynamic. The position in one point is replaced here by a position-in-movement (point-in-movement). "Movement is not indexed by position. Rather, the position is born in movement, from the relation of movement towards itself" (Massumi 179). Philosopher of "extended mind" Andy Clark notes that we should distinguish between a real body schema (non-conscious configuration) and a body image (conscious construct) (Clark). It is the former that is important to understand, and yet is the most challenging. Due to its fluidity and self-referentiality, proprioception is not presentable to consciousness (the unstable internal image that it creates resides in consciousness but cannot be grasped and thus re-presented). A feeling/sense, it is not bound by sensible forms that would serve as means of objectification and externalization. As Barbara Montero observes, while the objects of vision and hearing, i.e. the most popular senses involved in the arts, are beyond one's body, sense of proprioception relates directly to the bodily sensation, it does not represent any external objects, but the sensory itself (231). These characteristics of proprioception help to reframe the question of augmentation as mediation: in the case of proprioception, the medium of sensation is the very relational structure of the body itself, irrespective of the "exteroceptive" (tactile) or "interoceptive" (visceral) dimensions of sensibility. The body is understood, then, as the "body without image,” and its proprioceptive effect can then be described as "the sensibility proper to the muscles and ligaments" (Massumi 58). Proprioception in (Media) Art One of the most convincing ways of externalization and (re)presentation of the data of proprioception is through re-production of its structure and its artificial enhancement with the help of technology. This can be achieved in at least two ways: by setting up situations and environments that emphasize self-perspective and awareness of perception, and by presenting measurements of bio-data and inviting into dialogue with them. The first strategy may be connected to disorientation and shifted perspective that are created in immersive virtual environments that make the role of otherwise un-trackable, fluid sense of proprioception actually felt and cognized. These effects are closely related to the nuances of perception of space, for instance, to spatial illusion. Practice of spatial illusion in the arts traces its history as far back as Roman frescos, trompe l’oeil, as well as phantasmagorias, like magic lantern. Geometrically, the system of the 360º image is still the most effective in producing a sense of full immersion—either in spaces from panoramas, Stereopticon, Cinéorama to CAVE (Computer Augmented Virtual Environments), or in devices for an individual spectator’s usage, like a stereoscope, Sensorama and more recent Head Mounted Displays (HMD). All these devices provide a sense of hermetic enclosure and bodily engagement with its scenes (realistic or often fantastical). Their images are frameless and thus immeasurable (lack of the sense of proportion provokes feeling of disorientation), image apparatus and the image itself converge here into an almost inseparable total unity: field of vision is filled, and the medium becomes invisible (Grau 198-202; 248-255). Yet, the constructed image is even more frameless and more peculiarly ‘mental’ in environments created on the basis of objectless or "immaterial" media, like light or sound; or in installations prioritizing haptic sensation and in responsive architectures, i.e. environments that transform physically in reaction to their inhabitants. The examples may include works by Olafur Eliasson that are centered around the issues of conscious perception and employ various optical and other apparata (mirrors, curved surfaces, coloured glass, water systems) to shift the habitual perspective and make one conscious of the subtle changes in the environment depending on one's position in space (there have been instances of spectators in Eliasson's installations falling down after trying to lean against an apparent wall that turned out to be a mere optical construct.). Figure 1: Olafur Eliasson, Take Your Time, 2008. © Olafur Eliasson Studio. In his classic H2OExpo project for Delta Expo in 1997, the Dutch architect Lars Spuybroek experimented with the perception of instability. There is no horizontal surface in the pavilion; floors, composed of interconnected elliptical volumes, transform into walls and walls into ceilings, promoting a sense of fluidity and making people respond by falling, leaning, tilting and "experiencing the vector of one’s own weight, and becoming sensitized to the effects of gravity" (Schwartzman 63). Along the way, specially installed sensors detect the behaviour of the ‘walker’ and send signals to the system to contribute further to the agenda of imbalance and confusion by changing light, image projection, and sound.Figure 2: Lars Spuybroek, H2OExpo, 1994-1997. © NOX/ Lars Spuybroek. Philip Beesley’s Hylozoic Ground (2010) is also a responsive environment filled by a dense organic network of delicate illuminated acrylic tendrils that can extend out to touch the visitor, triggering an uncanny mixture of delight and discomfort. The motif of pulsating movement was inspired by fluctuations in coral reefs and recreated via the system of precise sensors and microprocessors. This reference to an unfamiliar and unpredictable natural environment, which often makes us feel cautious and ultra-attentive, is a reminder of our innate ability of proprioception (a deeply ingrained survival instinct) and its potential for a more nuanced, intimate, emphatic and bodily rooted communication. Figure 3: Philip Beesley, Hylozoic Ground, 2010. © Philip Beesley Architect Inc. Works of this kind stimulate awareness of both the environment and one's own response to it. Inviting participants to actively engage with the space, they evoke reactions of self-reflexivity, i.e. the self becomes the object of its own exploration and (potentially) transformation. Another strategy of revealing the processes of the "body without image" is through representing various kinds of bio-data, bodily affective reactions to certain stimuli. Biosignal monitoring technologies most often employed include EEG (Electroencephalogram), EMG (Electromyogram), GSR (Galvanic Skin Response), ECG (Electrocardiogram), HRV (Heart Rate Variability) and others. Previously available only in medical settings and research labs, many types of sensors (bio and environmental) now become increasingly available (bio-enabled products ranging from cardio watches—an instance of the "quantified self" trend—to brain wave-controlled video games). As the representatives of the DIY makers community put it: "By monitoring some phenomena (biofeedback) you can train yourself to modulate them, possibly improving your emotional state. Biosensing lets you interact more naturally with digital systems, creating cyborg-like extensions of your body that overcome disabilities or provide new abilities. You can also share your bio-signals, if you choose, to participate in new forms of communication" (Montgomery). What is it about these technologies besides understanding more accurately the unconscious and invisible signals? The critical question in relation to biofeedback data is about the adequacy of the transference of the initial signal, about the "new" brought by the medium, as well as the ontological status of the resulting representation. These data are reflections of something real, yet themselves have a different weight, also providing the ground for all sorts of simulative methods and creation of mixed realities. External representations, unlike internal, are often attributed a prosthetic nature that is treated as extensions of existing skills. Besides serving their direct purpose (for instance, maps give detailed picture of a distant location), these extensions provide certain psychological effects, such as disorientation, displacement, a shift in a sense of self and enhancement of the sense of presence. Artistic experiments with bio-data started in the 1960s most famously with employing the method of sonification. Among the pioneers were the composers Alvin Lucier, Richard Teitelbaum, David Rosenblum, Erkki Kurenemi, Pierre Henry, and others. Today's versions of biophysical performance may include not only acoustic, but also visual interpretation, as well as subtle narrative scenarios. An example can be Marco Donnarumma's Hypo Chrysos, a piece that translates visceral strain in sound and moving images. The title refers to the type of a punishing trial in one of the circles of hell in Dante's Divine Comedy: the eternal task of carrying heavy rocks is imitated by the artist-performer, while the audience can feel the bodily tension enhanced by sound and imagery. The state of the inner body is, thus, amplified, or augmented. The sense of proprioception experienced by the performer is translated into media perceivable by others. In this externalized form it can also be shared, i.e. released into a space of inter-subjectivity, where it receives other, collective qualities and is not perceived negatively, in terms of pressure. Figure 4: Marco Donnarumma, Hypo Chrysos, 2011. © Marco Donnarumma. Another example can be an installation Telephone Rewired by the artist-neuroscientist Sean Montgomery. Brainwave signals are measured from each visitor upon the entrance to the installation site. These individual data then become part of the collective archive of the brainwaves of all the participants. In the second room, the viewer is engulfed by pulsing light and sound that mimic endogenous brain waveforms of the previous viewers. As in the experience of Donnarumma's performance, this process encourages tuning in to the inner state of the other and finding resonating states in one's own body. It becomes a tool for self-exploration, self-knowledge, and self-control, as well as for developing skills of collective being, of shared body-mind topologies. Synchronization of mental and bodily states of multiple people serves here a broader and deeper goal of training collaborative and empathic abilities. An immersive experience, it triggers deep embodied neural circuits, reaching towards the most authentic reactions not mediated by conscious procedures and judgment. Figure 5: Sean Montgomery, Telephone Rewired, 2013. © Sean Montgomery. Conclusion The potential of biofeedback as a strategy for art projects is a rich area that artists have only begun to explore. The layer of the imaginary and the fictional (which makes art special and different from, for instance, science) can add a critical dimension to understanding the processes of augmentation and mediation. As the described examples demonstrate, art is an investigative journey that can be engaging, surprising, and awakening towards the more subtle and acute forms of thinking and feeling. This astuteness and percipience are especially needed as media and technologies penetrate and affect our very abilities to apprehend reality. We need new tools to make independent and individual judgment. The sense of proprioception establishes a productive challenge not only for science, but also for the arts, inviting a search for new mechanisms of representing the un-presentable and making shareable and communicable what is, by definition, individual, fluid, and ungraspable. Collaborative cognition emerging from the augmentation of proprioception that is enabled by biofeedback technologies holds distinct promise for exploration of not only subjective, but also inter-subjective states and aesthetic strategies of inducing them. References Beesley, Philip. Hylozoic Ground. 2010. Venice Biennale, Venice. Clark, Andy, and David J. Chalmers. “The Extended Mind.” Analysis 58.1 (1998):7-19. Donnarumma, Marco. Hypo Chrysos: Action Art for Vexed Body and Biophysical Media. 2011. Xth Sense Biosensing Wearable Technology. MADATAC Festival, Madrid. Eliasson, Olafur. Take Your Time, 2008. P.S.1 Contemporary Art Centre; Museum of Modern Art, New York. Grau, Oliver. Virtual Art: From Illusion to Immersion. Cambridge, Mass.: MIT Press, 2003. Massumi, Brian. Parables of the Virtual: Movement, Affect, Sensation. Durham: Duke University Press, 2002. Montero, Barbara. "Proprioception as an Aesthetic Sense." Journal of Aesthetics and Art Criticism 64.2 (2006): 231-242. Montgomery, Sean, and Ira Laefsky. "Biosensing: Track Your Body's Signals and Brain Waves and Use Them to Control Things." Make 26. 1 Oct. 2013 ‹http://www.make-digital.com/make/vol26?pg=104#pg104›. Sacks, Oliver. "The Disembodied Lady". The Man Who Mistook His Wife for a Hat and Other Clinical Tales. Philippines: Summit Books, 1985. Schwartzman, Madeline, See Yourself Sensing. Redefining Human Perception. London: Black Dog Publishing, 2011. Spuybroek, Lars. Waterland. 1994-1997. H2O Expo, Zeeland, NL.

Introduction Medical misinformation and conspiracies have thrived during the current infodemic as a result of the volume of information people have been exposed to during the disease outbreak. Given that SARS-CoV-2 (COVID-19) is a novel coronavirus discovered in 2019, much remains unknown about the disease. Moreover, a considerable amount of what was originally thought to be known has turned out to be inaccurate, incomplete, or based on an obsolete knowledge of the virus. It is in this context of uncertainty and confusion that conspiracies flourish. Michael Golebiewski and danah boyd’s work on ‘data voids’ highlights the ways that actors can work quickly to produce conspiratorial content to fill a void. The data void absent of high-quality data surrounding COVID-19 provides a fertile information environment for conspiracies to prosper (Chou et al.). Conspiracism is the belief that society and social institutions are secretly controlled by a powerful group of corrupt elites (Douglas et al.). Michael Barkun’s typology of conspiracy reveals three components: 1) the belief that nothing happens by accident or coincidence; 2) nothing is as it seems: the "appearance of innocence" is to be suspected; 3) the belief that everything is connected through a hidden pattern. At the heart of conspiracy theories is narrative storytelling, in particular plots involving influential elites secretly colluding to control society (Fenster). Conspiracies following this narrative playbook have flourished during the pandemic. Pharmaceutical corporations profiting from national vaccine rollouts, and the emergency powers given to governments around the world to curb the spread of coronavirus, have led some to cast these powerful commercial and State organisations as nefarious actors – 'big evil' drug companies and the ‘Deep State’ – in conspiratorial narratives. Several drugs believed to be potential treatments for COVID-19 have become entangled with conspiracy. At the start of the pandemic scientists experimented with repurposing existing drugs as potential treatments for COVID-19 because safe and effective vaccines were not yet available. A series of antimicrobials with potential activity against SARS-CoV-2 were tested in clinical trials, including lopinavir/ritonavir, favipiravir and remdesivir (Smith et al.). Only hydroxychloroquine and ivermectin transformed from potential COVID treatments into conspiracy objects. This article traces how the hydroxychloroquine and ivermectin conspiracy theories were amplified in the news media and online. It highlights how debunking processes contribute to amplification effects due to audience segmentation in the current media ecology. We conceive of these amplification and debunking processes as key components of a ‘Conspiracy Course’ (Baker and Maddox), identifying the interrelations and tensions between amplification and debunking practices as a conspiracy develops, particularly through mainstream news, social media and alternative media spaces. We do this in order to understand how medical claims about potential treatments for COVID-19 succumb to conspiracism and how we can intervene in their development and dissemination. In this article we present a commentary on how public discourse and actors surrounding two potential treatments for COVID-19: the anti-malarial drug hydroxychloroquine and the anti-parasitic drug ivermectin became embroiled in conspiracy. We examine public discourse and events surrounding these treatments over a 24-month period from January 2020, when the virus gained global attention, to January 2022, the time this article was submitted. Our analysis is contextually informed by an extended digital ethnography into medical misinformation, which has included social media monitoring and observational digital field work of social media sites, news media, and digital media such as blogs, podcasts, and newsletters. Our analysis focusses on the role that public figures and influencers play in amplifying these conspiracies, as well as their amplification by some wellness influencers, referred to as “alt.health influencers” (Baker), and those affiliated with the Intellectual Dark Web, many of whom occupy status in alternative media spaces. The Intellectual Dark Web (IDW) is a term used to describe an alternative influence network comprised of public intellectuals including the Canadian psychologist Jordan Peterson and the British political commentator Douglas Murray. The term was coined by the American mathematician and podcast host Eric Weinstein, who described the IDW as a group opposed to “the gated institutional narrative” of the mainstream media and the political establishment (Kelsey). As a consequence, many associated with the IDW use alternative media, including podcasts and newsletters, as an "eclectic conversational space" where those intellectual thinkers excluded from mainstream conversational spaces in media, politics, and academia can “have a much easier time talking amongst ourselves” (Kelsey). In his analysis of the IDW, Parks describes these figures as "organic" intellectuals who build identification with their audiences by branding themselves as "reasonable thinkers" and reinforcing dominant narratives of polarisation. Hence, while these influential figures are influencers in so far as they cultivate an online audience as a vocation in exchange for social, economic and political gain, they are distinct from earlier forms of micro-celebrity (Senft; Marwick) in that they do not merely achieve fame on social media among a niche community of followers, but appeal to those disillusioned with the mainstream media and politics. The IDW are contrasted not with mainstream celebrities, as is the case with earlier forms of micro-celebrity (Abidin Internet Celebrity), but with the mainstream media and politics. A public figure, on the other hand, is a “famous person” broadcast in the media. While celebrities are public figures, public figures are not necessarily celebrities; a public figure is ‘a person of great public interest or familiarity’, such as a government official, politician, entrepreneur, celebrity, or athlete. Analysis In what follows we explore the role of influencers and public figures in amplifying the hydroxychloroquine and ivermectin conspiracy theories during the pandemic. As part of this analysis, we consider how debunking processes can further amplify these conspiracies, raising important questions about how to most effectively respond to conspiracies in the current media ecology. Discussions around hydroxychloroquine and ivermectin as potential treatments for COVID-19 emerged in early 2020 at the start of the pandemic when people were desperate for a cure, and safe and effective vaccines for the virus were not yet publicly available. While claims concerning the promising effects of both treatments emerged in the mainstream, the drugs remained experimental COVID treatments and had not yet received widespread acceptance among scientific and medical professionals. Much of the hype around these drugs as COVID “cures” emerged from preprints not yet subject to peer review and scientific studies based on unreliable data, which were retracted due to quality issues (Mehra et al.). Public figures, influencers, and news media organisations played a key role in amplifying these narratives in the mainstream, thereby extending the audience reach of these claims. However, their transformation into conspiracy objects followed different amplification processes for each drug. Hydroxychloroquine, the “Game Changer” Hydroxychloroquine gained public attention on 17 March 2020 when the US tech entrepreneur Elon Musk shared a Google Doc with his 40 million followers on Twitter, proposing “maybe worth considering chloroquine for C19”. Musk’s tweet was liked over 50,200 times and received more than 13,500 retweets. The tweet was followed by several other tweets that day in which Musk shared a series of graphs and a paper alluding to the “potential benefit” of hydroxychloroquine in in vitro and early clinical data. Although Musk is not a medical expert, he is a public figure with status and large online following, which contributed to the hype around hydroxychloroquine as a potential treatment for COVID-19. Following Musk’s comments, search interest in chloroquine soared and mainstream media outlets covered his apparent endorsement of the drug. On 19 March 2020, the Fox News programme Tucker Carlson Tonight cited a study declaring hydroxychloroquine to have a “100% cure rate against coronavirus” (Gautret et al.). Within hours another public figure, the then-US President Donald Trump, announced at a White House Coronavirus Task Force briefing that the FDA would fast-track approval of hydroxychloroquine, a drug used to treat malaria and arthritis, which he said had, “tremendous promise based on the results and other tests”. Despite the Chief Medical Advisor to the President, Dr Anthony Fauci, disputing claims concerning the efficacy of hydroxychloroquine as a potential therapy for coronavirus as “anecdotal evidence”, Trump continued to endorse hydroxychloroquine describing the drug as a “game changer”: HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. He said that the drugs should be put in use IMMEDIATELY. PEOPLE ARE DYING, MOVE FAST, and GOD BLESS EVERYONE! Trump’s tweet was shared over 102,800 times and liked over 384,800 times. His statements correlated with a 2000% increase in prescriptions for the anti-malarial drugs hydroxychloroquine and chloroquine in the US between 15 and 21 March 2020, resulting in many lupus patients unable to source the drug. There were also reports of overdoses as individuals sought to self-medicate with the drug to treat the virus. Once Trump declared himself a proponent of hydroxychloroquine, scientific inquiry into the drug was eclipsed by an overtly partisan debate. An analysis by Media Matters found that Fox News had promoted the drug 109 times between 23 and 25 March 2020, with other right wing media outlets following suit. The drug was further amplified and politicised by conservative public figures including Trump’s attorney Rudy Giuliani, who claimed on 27 March 2020 that “hydroxychloroquine has been shown to have a 100% effective rate in treating COVID-19”, and Brazil’s President, Jair Bolsonaro, who shared a Facebook post on 8 July 2020 admitting to taking the drug to treat the virus: “I’m one more person for whom this is working. So I trust hydroxychloroquine”. In addition to these conservative political figures endorsing hydroxychloroquine, on 27 July 2020 the right-wing syndicated news outlet Breitbart livestreamed a video depicting America’s Frontline Doctors – a group of physicians backed by the Tea Party Patriots, a conservative political organisation supportive of Trump – at a press conference outside the US Supreme Court in Washington. In the video, Stella Immanuel, a primary care physician in Texas, said “You don’t need masks…There is prevention and there is a cure!”, explaining that Americans could resume their normal lives by preemptively taking hydroxychloroquine. The video was retweeted by public figures including President Trump and Trump’s son Donald Trump Jr., before going viral reaching over 20 million users on Facebook. The video explicitly framed hydroxychloroquine as an effective “cure” for COVID-19 suppressed by “fake doctors”, thereby transferring it from potential treatment to a conspiracy object. These examples not only demonstrate the role of prominent public figures in amplifying conspiratorial claims about hydroxychloroquine as an effective cure for COVID-19, they reveal how these figures converted the drug into an “article of faith” divorced from scientific evidence. Consequently, to believe in its efficacy as a cure for COVID-19 demonstrated support for Trump and ideological skepticism of the scientific and medical establishment. Ivermectin, the “Miracle Cure” Ivermectin followed a different amplification trajectory. The amplifying process was primarily led by influencers in alternative media spaces and those associated with the IDW, many of whom position themselves in contrast to the mainstream media and politics. Despite scientists conducting clinical trials for ivermectin in early 2020, the ivermectin conspiracy peaked much later that year. On 8 December 2020, the pulmonary and ICU specialist Dr. Pierre Kory testified to the US Senate Committee about I-MASK: a prevention and early outpatient treatment protocol for COVID-19. During the hearing, Kory claimed that “ivermectin is effectively a ‘miracle drug’ against COVID-19”, which could end the pandemic. Kory’s depiction of ivermectin as a panacea, and the subsequent media hype, elevated him as a public figure and led to an increase in public demand for ivermectin in early 2021. This resulted in supply issues and led some people to seek formulations of the drug designed for animals, which were in greater supply and easier to access. Several months later in June 2021, Kory’s description of ivermectin as a “miracle cure” was amplified by a series of influencers, including Bret Weinstein and Joe Rogan, both of whom featured Kory on their podcasts as a key public figure in the fight against COVID Conspiratorial associations with ivermectin were further amplified on 9 July 2021 when Bret Weinstein appeared on Fox Nation's Tucker Carlson Today claiming he had “been censored for raising concerns about the shots and the medical establishment's opposition to alternative treatments”. The drug was embroiled in further controversy on 1 September 2021 when Joe Rogan shared an Instagram post explaining that he had taken ivermectin as one of many drugs to treat the virus. In the months that followed, Rogan featured several controversial scientists on his podcast who implied that ivermectin was an effective COVID “cure” suppressed as part of a global agenda to promote vaccine uptake. These public figures included Dr Robert Malone, an American physician who contributed to the development of mRNA technology, and Dr Peter McCullough, an American cardiologist with expertise in vaccines. As McCullough explained to Rogan in December 2021: it seemed to me early on that there was an intentional very comprehensive suppression of early treatment in order to promote fear, suffering, isolation, hospitalisation and death and it seemed to be completely organised and intentional in order to create acceptance for and then promote mass vaccination. McCullough went on to imply that the pandemic was planned and that vaccine manufacturers were engaged in a coordinated response to profit from mass vaccination. Consequently, whereas conservative public figures, such as Trump and Bolsonaro, played a primary role in amplifying the hype around hydroxychloroquine as a COVID cure and embroiling it in a political and conspiratorial narrative of collusion, influencers, especially those associated with alternative media and the IDW, were crucial in amplifying the ivermectin conspiracy online by platforming controversial scientists who espoused the drug as a “miracle cure”, which could allegedly end the pandemic but was being suppressed by the government and medical establishment. Debunking Debunking processes refuting the efficacy of these drugs as COVID “cures” contributed to the amplification of these conspiracies. In April 2020 the paper endorsing hydroxychloroquine that Trump tweeted about a week earlier was debunked. The debunking process for hydroxychloroquine involved a series of statements, papers, randomised clinical trials and retractions not only rejecting the efficacy of hydroxychloroquine, but suggesting it was unsafe and had the potential to cause harm (Boulware et al.; Mehra; Voss). In April 2020, the FDA released a statement cautioning against the use of hydroxychloroquine for COVID-19 outside of a hospital setting or a clinical trial due to risk of heart rhythm problems, and in June the FDA revoked its emergency use authorisation to treat COVID-19 in certain hospitalised patients. The debunking process was not limited to fact-based claims, it also involved satire and ridicule of those endorsing the drug as a treatment for COVID-19. Given the politicisation of the drug, much of this criticism was directed at Trump, as a key proponent of the drug, and Republicans in general, both of whom were cast as scientifically illiterate. The debunking process for ivermectin was similarly initiated by scientific and medical authorities who questioned the efficacy of ivermectin as a COVID-19 treatment due to reliability issues with trials and the quality of evidence (Lawrence). In response to claims that supply issues led people to seek formulations of the drug designed for animals, in April 2021 the FDA released a statement cautioning people not to take ivermectin to prevent or treat COVID-19: While there are approved uses for ivermectin in people and animals, it is not approved for the prevention or treatment of COVID-19 … . People should never take animal drugs … . Using these products in humans could cause serious harm. The CDC echoed this warning, claiming that “veterinary formulations intended for use in large animals such as horses, sheep, and cattle can be highly concentrated and result in overdoses when used by humans”. Many journalists and Internet users involved in debunking ivermectin reduced the drug to horse paste. Social media feeds debunking ivermectin were filled with memes ridiculing those consuming “horse dewormer”. Mockery of those endorsing ivermectin extended beyond social media, with the popular US sketch comedy show Saturday Night Live featuring a skit mocking Joe Rogan for consuming “horse medicine” to treat the virus. The skit circulated on social media in the following days, further deriding advocates of the drug as a COVID cure as not only irresponsible, but stupid. This type of ridicule, visually expressed in videos and Internet memes, fuelled polarisation. This polarisation was then weaponised by influencers associated with the IDW to sell ivermectin as a “miracle drug” suppressed by the medical and political establishment, thereby embroiling the drug further in conspiracy (Baker and Maddox). This type of opportunistic marketing is not intended for a mass audience. Instead, audiences are taking advantage of what Crystal Abidin refers to as “silosociality”, wherein content is tailored for specific subcommunities, which are not necessarily “accessible” or “legible” to outsiders (Abidin Refracted Publics 4). This dynamic both reflects and reinforces the audience segmentation that occurs in the current media ecology by virtue of alternative media with mockery and ridicule strengthening in- and out-group dynamics. Conclusion In this article we have traced how hydroxychloroquine and ivermectin moved from promising potential COVID-19 treatments to objects tainted by conspiracy. Despite common associations of conspiracy theories with the fringe, both the hydroxychloroquine and ivermectin conspiracy theories emerged in the mainstream, amplified across mainstream social networks with the help of influencers and public figures whose claims were further amplified by the news media commenting on their apparent endorsement of these drugs as COVID cures. Whereas hydroxychloroquine was politicised as a result of controversial public figures and right-wing media outlets endorsing the drug and the conspiratorial narrative espoused by America’s Frontline Doctors, notably much of the conspiracy around ivermectin shifted to alternative media spaces amplified by influencers disillusioned with the mainstream media. We have demonstrated how debunking processes, which sought to discredit these drugs as potential treatments for COVID-19, often ridiculed those who endorsed them, further polarising discussions involving these treatments and pushing advocates to the extreme. By encouraging proponents of these treatments to retreat to alternative media spaces, such as podcasts and newsletters, polarisation strengthened in-group dynamics, assisting the ability for opportunistic influencers to weaponise these conspiracies for social, economic, and political gain. These findings raise important questions about how to effectively counter conspiracies. When debunking not only refutes claims but ridicules advocates, debunking can have unintended consequences by strengthening in-group dynamics and fuelling the legitimacy of conspiratorial narratives. References Abidin, Crystal. Internet Celebrity: Understanding Fame Online. Emerald Group Publishing, 2018. Abidin, Crystal. "From ‘Networked Publics’ to ‘Refracted Publics’: A Companion Framework for Researching ‘below the Radar’ Studies." Social Media + Society 7.1 (2021). Baker, Stephanie Alice. "Alt.Health Influencers: How Wellness Culture and Web Culture Have Been Weaponised to Promote Conspiracy Theories and Far-Right Extremism during the COVID-19 Pandemic." European Journal of Cultural Studies 25.1 (2022): 3-24. Baker, Stephanie Alice, and Alexia Maddox. “COVID-19 Treatment or Miracle 'Cure'?: Tracking the Hydroxychloroquine, Remdesivir and Ivermectin Conspiracies on Social Media.” Paper presented at the BSA Annual Conference 2022: Building Equality and Justice Now, 20-22 April 2022. <https://www.britsoc.co.uk/media/25695/ac2022_draft_conf_prog.pdf>. Barkun, Michael. A Culture of Conspiracy. University of California Press, 2013. Boulware, David R., et al. "A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19." New England Journal of Medicine 383.6 (2020): 517-525. Chou, Wen-Ying Sylvia, Anna Gaysynsky, and Robin C. Vanderpool. "The COVID-19 Misinfodemic: Moving beyond Fact-Checking." Health Education & Behavior 48.1 (2021): 9-13. Douglas, Karen M., et al. "Understanding Conspiracy Theories." Political Psychology 40 (2019): 3-35. Fenster, Mark. Conspiracy Theories: Secrecy and Power in American Culture. University of Minnesota Press, 1999. Gautret, Philippe, et al. "Hydroxychloroquine and Azithromycin as a Treatment of COVID-19: Results of an Open-Label Non-Randomized Clinical Trial." International Journal of Antimicrobial Agents 56.1 (2020): 105949. Golebiewski, Michael, and danah boyd. "Data Voids: Where Missing Data Can Easily Be Exploited." Data & Society (2019). Kelsey, Darren. "Archetypal Populism: The ‘Intellectual Dark Web’ and the ‘Peterson Paradox’." Discursive Approaches to Populism across Disciplines. Cham: Palgrave Macmillan, 2020. 171-198. Lawrence, Jack M., et al. "The Lesson of Ivermectin: Meta-Analyses Based on Summary Data Alone Are Inherently Unreliable." Nature Medicine 27.11 (2021): 1853-1854. Marwick, Alice E. Status Update. Yale University Press, 2013. Mehra, Mandeep R., et al. "RETRACTED: Hydroxychloroquine or Chloroquine with or without a Macrolide for Treatment of COVID-19: A Multinational Registry Analysis." (2020). Parks, Gabriel. "Considering the Purpose of ‘an Alternative Sense-Making Collective’: A Rhetorical Analysis of the Intellectual Dark Web." Southern Communication Journal 85.3 (2020): 178-190. Senft, Theresa M. Camgirls: Celebrity and Community in the Age of Social Networks. Peter Lang, 2008. Smith, Tim, et al. "COVID-19 Drug Therapy." Elsevier (2020). Voss, Andreas. “Official Statement from International Society of Antimicrobial Chemotherapy (ISAC).” International Society of Antimicrobial Chemotherapy 3 Apr. 2020. <https://www.isac.world/news-and-publications/official-isac-statement>.

An elderly man of my acquaintance once told me that there was nothing much to recommend living beyond 90. Things have changed over the past two decades, however. These days all he'd need is a touch of Viagra, an attitude reorientation, a little bit of manifesting and he'd be feeling as fit as, as, well … as a man in his 60s. Had he been around now, as a knowledgeable nonagenarian, he need not have mourned the passing of the years. Instead, he could have concentrated on becoming daily younger. As Second Youth so blithely trumpets: "In your youth, your mind, body and spirit are capable of great recuperative powers but, as you get older, you believe that those powers diminish. Not true! As long as you have a will -- and a method -- to improve your life, you will find the power to make it happen." Lacking the method? Look no longer… Books entitled RealAge: Are You as Young as You Can Be? (Roizen 1999) appear at the top of the New York Times best seller list, arguing that some 70-year olds can have the health profile of average 44-year olds within three years of making the right choices. (www.RealAge.com) This is the book's manifesto: The whole point of RealAge is to promote old age. Healthy, vibrant and young old age. RealAge shows you how you can live at eighty with all the energy and vigor of a fifty-five year old, how you can be the ninety year old who still lives on your own, travels and forcefully expresses feisty opinions -- the person who leaves the 'kids' marveling, 'How does she do it?' Having respect for old age means wanting to end the suffering that so often goes along with it. No one wants to be bedridden, afflicted with heart disease, or undergoing cancer treatment. Everyone wants to be able to do all the things he or she has always done and more. [Italics, gendered language, original] (Roizen 1999, p. 10) This website-supported best seller is part of a burgeoning industry which includes Cassel and Vallasi (1999) The Practical Guide to Aging: What Everyone Needs to Know, and Perls and Silver (1999) Living to 100: Lessons in Living to Your Maximum Potential at Any Age. "‘People have gotten old before, but never this many people and never this many people with such a high level of education … [boomers] will become obsessed with health and prevention of all the infirmities that accompany aging’ predicts Russell." (Wetzstein 1999, citing Russell.) The hypothesis put forward by Russell, by Wetzstein (1999) and by others, is that this is an 'age and stage' issue. It represents a new generational perspective reflective of the mindset and the life experience of the post mid-1940s 'baby boomer'. This website-supported best seller is part of a burgeoning industry which includes Cassel and Vallasi (1999) The Practical Guide to Aging: What Everyone Needs to Know, and Perls and Silver (1999) Living to 100: Lessons in Living to Your Maximum Potential at Any Age. "‘People have gotten old before, but never this many people and never this many people with such a high level of education … [boomers] will become obsessed with health and prevention of all the infirmities that accompany aging’ predicts Russell." (Wetzstein 1999, citing Russell.) The hypothesis put forward by Russell, by Wetzstein (1999) and by others, is that this is an 'age and stage' issue. It represents a new generational perspective reflective of the mindset and the life experience of the post mid-1940s 'baby boomer'. Boomers refuse to see 40 as middle aged (Wetzstein 1999), and would perish the thought that the Rolling Stones would ever retire. They define 50s as ‘Second youth’. (Gabriel & Molli 1995) They continue to participate in adventure and encounter holidays and subscribe to complementary health care regimes and new age approaches to daily life. They sign up for www.lovinguniversity.net and marvel at how much younger 43-yr old founder Susan Bradley looks on her website than in a recent Who Weekly (2001, p. 71). This baby boomer refusal to age has manifested itself widely in general and specialist consumer magazines, in broadcast TV and radio shows concentrating on good health and super-fitness, and in other elements of popular culture. Even given the hype, however, this new perspective might have long-term beneficial health/medical effects. The aging of the boomer generation may not be accurately predictable from the data collected from other generations with other mindsets. The back cover of Second Youth proclaims: "Desperate and aging far too fast she staked everything on discovering a natural source of Young Women's Hormones. Now, her triumph gives you thirty extra years of Second Youth. Age moved backwards for this woman. Just as it can -- this very month -- for you". (Gabriel & Molli 1995, back cover) Did someone mention snake oil? Or Bluebeard? Coupled with an optimism that allows them to forecast health and happiness into double-digit decades, however, boomers have a demonstrable suspicion of conventional medical ‘authority’ and a willingness to do their own research on health topics of interest. According to Mycek (1999) "In 1998, the [US] bill for homeopathic remedies (chiropractic and massage therapy, vitamins, yoga, herbal remedies, hypnosis, acupuncture) exceeded the total gross domestic product of all [US] hospitals put together." For boomers, a greater emphasis on health is not going to mean more of the same health care products, delivered in the same way. It is going to mean doing things differently. But is this a healthy way for us to look at aging and (shall we mention the word) death? Is our desire/burning commitment to remain indefinitely young and healthy in some way 'sick'? It is eminently reasonable to hypothesise -- as many people approaching their 'middle years' do -- that baby boomers are aiming to reinvent the aging process. (Dychtwald, 1999) The past quarter century has seen the burgeoning growth of preventative/health promotion and complementary health promoting services including nutritionists, naturopaths, chiropractors, rebalancers, meditation teachers, physiotherapists, counsellors and life coaches. The oldest members of the richest, best informed, most numerous generation in history are turning 55. The boomers (born from 1946--1960) can't put off for any longer the fact that -- chronologically -- they are approaching middle age. But what does this mean to a generation with many members who would rather be dead than old? Does the denial of chronological age, and the espousal of 'physiological age' (the premise upon which the RealAge philosophy and empire is built) represent a sick fantasy to avoid accepting our mortality? Baby boomers are a specific, much researched, sociocultural phenomenon. Their aim is to move beyond actuarial projections to re-write expectations of aging. From the self-help movement to the success of the potency drug Viagra, there is ample evidence that boomers have plans and expectations for their own aging processes that differ radically from those adopted by their parents. People born into the prosperity and plenty of the early post-WWII years often police their health attitudes and behaviours in proactive ways. These patterns are likely to impact upon their health profiles in the future and to influence the creation of services tailored to meet different hopes, fears and expectations. Who says Cher can't look young forever? Most health care planning is based on actuarial data that examines past events and extrapolates from these events into the future. However, this is not likely to result in a valid prediction of the health and aging patterns of the boomer generation. Graham May is a futurologist. He suggests that (May 2000), in anticipating the future, we are attempting either to foresee it, to manage it, or to create it. The philosophical distinctions between these perspectives provide different rationales for those who wish to influence the future. Attempts to foresee, or predict, the future – for example by extrapolating trends – presuppose that in some very particular ways the future already exists and/or is closely related to the forces evident in the present and the past. Managing the present with the future in mind accepts that present actions and decisions influence the future, and suggests that the future does not exist and is capable of being influenced by our current choices. The creation of the future – through techniques such as ‘creative visioning’ – works on the basis that once situations that do not exist have been imagined they can be brought into existence. These three approaches, separately and in parallel, offer ways of negotiating the uncertainty and essential unpredictability of the future, and of longevity and fitness. The longevity and second youth approach combines the idea of managing the future and envisioning it: 'the manifestation' approach. Baby boomers have already created a different future for our society. They are credited with re-writing the institutions of marriage (via de factos, divorce, blended families, single parents, older pregnancies); marketing (psychodemographics rather than age, sex, socioeconomic status); religion (the decline of the Church and the rise of new age philosophies, faith healing, angels on demand); education (just-in-time learning, lifelong learning); work practices -- and health. The boomers are also rewriting what aging means for them, and to them. Using popular culture starting points, such as Second Youth and RealAge, it seems that a major boomer project of the next twenty years is working to defy/turn back the aging clock. This project is invested with the hopes, fears, dreams and expectations of millions of citizens in western societies. Boomers are practical, however, as well as ‘just in time’ and they know that a belief that they can do it is half the battle. Let's assume that although many boomers are already fitter and healthier than any generation before them at their age, others may be intending to ‘make a break’ for fitness as an early priority of their retirement. Boomers may also expect their retirement years to be years of health and plenty, and they seem to indicate that they're prepared actively to work with these goals in mind. However, not all will be successful in beating their biology. How do boomers expect to manage their own chronic ailments in the future: arthritis, failing hearing and sight, late onset diabetes, heart disease, incontinence, dementia etc? Will the stem cell implants solve all foreseeable problems? Excluding alternative and complementary medical strategies, the health care industry is one of the biggest sectors of the economy representing 8% GDP (and rising). As indicated by its growing place in popular culture, health is also a hobby, pastime and pleasure – and the contemporary obsession with health is … sick. Although the social advantage to be conferred by living as healthily as possible, and as well as possible, is self-evident, it may require a level of selfishness and self-absorption unparalleled in human history. More to the point, however, this approach to getting older brings problems of its own. Firstly, it is built on a fear of aging, and a wish to deny the aging process which may become more desperate as the years (and they will) take their toll. Far from increasing the pleasure and satisfaction of 'a good age' this dynamic, operating over the decades, is as likely to build frustration, depression and a sense of powerlessness. As a (breast) cancer patient once told me: 'It's bad enough having cancer without everyone else thinking it's my fault for not having a positive enough attitude!' Aging is going to happen -- will we go with the flow - or end up like King Canute, with wet feet, trying to turn back the tide? Secondly, this perspective is counter-productive in fetishising a numerical age. When we're so focused on chronological age, biological age and the celebrating of our first, second and third 'year younger' parties (with fruit and water, please) we're not coming to terms with what's real for us in our ecological niche. Humanity is comprised of sentient, vertebrate, mammals. Far better to know our life cycle, and plan our lives to fit within it, than to pretend it can be revered. Much better to accept that we can be a very fit seventy year old (or a very unfit seventy year old) than to persuade ourselves that 'That's just my chronology, my real age is 44.' I'm sure we'll all be able to tell the difference… If anyone seriously believed the hype of living 26 years younger, you'd have to feel more than sorry for them. You'd have to suspect that maybe, even if they were blissfully unaware of it, they're a little bit sick. I gather that there's a Centre for Positive Aging recently started up in Perth: that's something altogether healthier References Cassel, C. and Vallasi, G. The Practical Guide to Aging: What Everyone Needs to Know. New York: New York University Press, 1999. Dychtwald, K. 'Age power': how the new-old will transform medicine in the 21st century, Geriatrics, vol. 54, no. 12, 1999, 22—7. Gabriel, V. and Molli, J. Second Youth, Melbourne: Bookman Press, 1995. May, G. Worldviews, assumptions and typologies of the future, Journal of Future Studies, vol. 5, no. 2, November, 2000, 37—51 Mycek, S. We’re not in Kansas anymore, Trustee, vol. 52, no. 8, 1999, 20—4 Perls, T. and Silver, M. Living to 100: Lessons in Living to Your Maximum Potential at Any Age, New York: Basic Books, 1999. Roizen, M. RealAge: Are You as Young as You Can Be? London: Thorsons, 1999 Wetzstein, C. Boomers’ new quest: to be forever young, Insight on the News, vol. 15, no. 24, 28th June, 1999, 40 Who Weekly Love is in the air, no. 474, 2 April, 2001, 71

ABSTRACT I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments. INTRODUCTION In contrast to the classic model of randomized-control trials, often with a large number of subjects enrolled, precision medicine attempts to optimize therapeutic outcomes by focusing on the individual.[i] A recent publication highlights the strengths and weakness of both traditional evidence-based medicine and precision medicine.[ii] Plus, it outlines a tension in the shift from evidence-based medicine’s inductive reasoning style (the collection of data to postulate general theories) to precision medicine’s abductive reasoning style (the generation of an idea from the limited data available).[iii] The paper’s main example is the application of precision medicine for the treatment of cancer.[iv] I argue that this examination and appreciation for the shift to abductive reasoning should be extended to the intersection of neuroscience and novel brain-computer interfaces too. As the name suggests, brain-computer interfaces are a significant advancement in neurotechnology that directly connects someone’s brain to external or implanted devices.[v] Among the various kinds of brain-computer interfaces, adaptive deep brain stimulation devices require numerous personalized adjustments to their settings during the implantation and computation stages in order to provide adequate relief to patients with treatment-resistant disorders. What makes these devices unique is how adaptive deep brain stimulation integrates a sensory component to initiate the stimulation. While not commonly at the level of sophistication as self-supervising or generative large language models,[vi] they currently allow for a semi-autonomous form of neuromodulation. This paper highlights the implications of applying abductive reasoning to personalized implantable neurotechnologies. Then, it explores whether abductive reasoning is sufficient to justify insurance coverage for devices absent widespread clinical trials, which are better applied to one-size-fits-all treatments.[vii] ANALYSIS I. The State of Precision Medicine in Oncology and the Epistemological Shift While a thorough overview of precision medicine for the treatment of cancer is beyond the scope of this article, its practice can be roughly summarized as identifying clinically significant characteristics a patient possesses (e.g., genetic traits) to land on a specialized treatment option that, theoretically, should benefit the patient the most.[viii] However, in such a practice of stratification patients fall into smaller and smaller populations and the quality of evidence that can be applied to anyone outside these decreases in turn.[ix] As inductive logic helps to articulate, the greater the number of patients that respond to a particular therapy the higher the probability of its efficacy. By straying from this logical framework, precision medicine opens the treatment of cancer to more uncertainty about the validity of these approaches to the resulting disease subcategories.[x] Thus, while contemporary medical practices explicitly describe some treatments as “personalized”, they ought not be viewed as inherently better founded than other therapies.[xi] A relevant contemporary case of precision medicine out of Norway focuses on the care of a patient with cancer between the ventricles of the heart and esophagus, which had failed to respond to the standard regimen of therapies over four years.[xii] In a last-ditch effort, the patient elected to pay out-of-pocket for an experimental immunotherapy (nivolumab) at a private hospital. He experienced marked improvements and a reduction in the size of the tumor. Understandably, the patient tried to pursue further rounds of nivolumab at a public hospital. However, the hospital initially declined to pay for it given the “lack of evidence from randomised clinical trials for this drug relating to this [patient’s] condition.”[xiii] In rebuttal to this claim, the patient countered that he was actually similar to a subpopulation of patients who responded in “open‐label, single arm, phase 2 studies on another immune therapy drug” (pembrolizumab).[xiv] Given this interpretation of the prior studies and the patient’s response, further rounds of nivolumab were approved. Had the patient not had improvements in the tumor’s size following a round of nivolumab, then pembrolizumab’s prior empirical evidence in isolation would have been insufficient, inductively speaking, to justify his continued use of nivolumab.[xv] The case demonstrates a shift in reasoning from the traditional induction to abduction. The phenomenon of ‘cancer improvement’ is considered causally linked to nivolumab and its underlying physiological mechanisms.[xvi] However, “the weakness of abductions is that there may always be some other better, unknown explanation for an effect. The patient may for example belong to a special subgroup that spontaneously improves, or the change may be a placebo effect. This does not mean, however, that abductive inferences cannot be strong or reasonable, in the sense that they can make a conclusion probable.”[xvii] To demonstrate the limitations of relying on the abductive standard in isolation, commentators have pointed out that side effects in precision medicine are hard to rule out as being related to the initial intervention itself unless trends from a group of patients are taken into consideration.[xviii] As artificial intelligence (AI) assists the development of precision medicine for oncology, this uncertainty ought to be taken into consideration. The implementation of AI has been crucial to the development of precision medicine by providing a way to combine large patient datasets or a single patient with a large number of unique variables with machine learning to recommend matches based on statistics and probability of success upon which practitioners can base medical recommendations.[xix] The AI is usually not establishing a causal relationship[xx] – it is predicting. So, as AI bleeds into medical devices, like brain-computer interfaces, the same cautions about using abductive reasoning alone should be carried over. II. Responsive Neurostimulation, AI, and Personalized Medicine Like precision medicine in cancer treatment, computer-brain interface technology similarly focuses on the individual patient through personalized settings. In order to properly expose the intersection of AI, precision medicine, abductive reasoning, and implantable neurotechnologies, the descriptions of adaptive deep brain stimulation systems need to deepen.[xxi] As a broad summary of adaptive deep brain stimulation, to provide a patient with the therapeutic stimulation, a neural signal, typically referred to as a local field potential,[xxii] must first be detected and then interpreted by the device. The main adaptive deep brain stimulation device with premarket approval, the NeuroPace Responsive Neurostimulation system, is used to treat epilepsy by detecting and storing “programmer-defined phenomena.”[xxiii] Providers can optimize the detection settings of the device to align with the patient’s unique electrographic seizures as well as personalize the reacting stimulation’s parameters.[xxiv] The provider adjusts the technology based on trial and error. One day machine learning algorithms will be able to regularly aid this process in myriad ways, such as by identifying the specific stimulation settings a patient may respond to ahead of time based on their electrophysiological signatures.[xxv] Either way, with AI or programmers, adaptive neurostimulation technologies are individualized and therefore operate in line with precision medicine rather than standard treatments based on large clinical trials. Contemporary neurostimulation devices are not usually sophisticated enough to be prominent in AI discussions where the topics of neural networks, deep learning, generative models, and self-attention dominate the conversation. However, implantable high-density electrocorticography arrays (a much more sensitive version than adaptive deep brain stimulation systems use) have been used in combination with neural networks to help patients with neurologic deficits from a prior stroke “speak” through a virtual avatar.[xxvi] In some experimental situations, algorithms are optimizing stimulation parameters with increasing levels of independence.[xxvii] An example of neurostimulation that is analogous to the use of nivolumab in Norway surrounds a patient in the United States who was experiencing both treatment-resistant OCD and temporal lobe epilepsy.[xxviii]Given the refractory nature of her epilepsy, implantation of an adaptive deep brain stimulation system was indicated. As a form of experimental therapy, her treatment-resistant OCD was also indicated for the off-label use of an adaptive deep brain stimulation set-up. Another deep brain stimulation lead, other than the one implanted for epilepsy, was placed in the patient’s right nucleus accumbens and ventral pallidum region given the correlation these nuclei had with OCD symptoms in prior research. Following this, the patient underwent “1) ambulatory, patient-initiated magnet-swipe storage of data during moments of obsessive thoughts; (2) lab-based, naturalistic provocation of OCD-related distress (naturalistic provocation task); and (3) lab-based, VR [virtual reality] provocation of OCD-related distress (VR provocation task).”[xxix] Such signals were used to identify when to deliver the therapeutic stimulation in order to counter the OCD symptoms. Thankfully, following the procedure and calibration the patient exhibited marked improvements in their OCD symptoms and recently shared her results publicly.[xxx] In both cases, there is a similar level of abductive justification for the efficacy of the delivered therapy. In the case study in which the patient was treated with adaptive deep brain stimulation, they at least had their neural activity tested in various settings to determine the optimum parameters for treatment to avoid them being based on guesswork. Additionally, the adaptive deep brain stimulation lead was already placed before the calibration trials were conducted, meaning that the patient had already taken on the bulk of the procedural risk before the efficacy could be determined. Such an efficacy test could have been replicated in the first patient’s cancer treatment, had it been biopsied and tested against the remaining immunotherapies in vitro. Yet, in the case of cancer with few options, one previous dose of a drug that appeared to work on the patient may justify further doses. However, as the Norwegian case presents, corroboration with known responses to a similar drug (from a clinical trial) could be helpful to validate the treatment strategy. (It should be noted that both patients were resigned to these last resort options regardless of the efficacy of treatment.) There are some elements of inductive logic seen with adaptive deep brain stimulation research in general. For example, abductively the focus could be that patient X’s stimulation parameters are different from patient Y’s and patient Z’s. In contrast, when grouped as subjects who obtained personalized stimulation, patients X, Y, and Z demonstrate an inductive aspect to this approach’s safety and/or efficacy. The OCD case holds plenty of abductive characteristics in line with precision medicine’s approach to treating cancer and as more individuals try the method, there will be additional data. With the gradual integration of AI into brain-computer interfaces in the name of efficacy, this reliance on abduction will continue, if not grow, over time. Moving forward, if a responsive deep brain stimulation treatment is novel and individualized (like the dose of nivolumab) and there is some other suggestion of efficacy (like clinical similarities to other patients in the literature), then it may justify insurance coverage for the investigative intervention, absent other unrelated reasons to deny it. III. Ethical Implications and Next Steps While AI’s use in oncology and neurology is not yet as prominent as its use in other fields (e.g., radiology), it appears to be on the horizon for both.[xxxi] AI can be found in both the functioning of the neurotechnologies as well as the implementation of precision medicine. The increasing use of AI may serve to further individualize both oncologic and neurological therapies. Given these implications and the handful of publications cited in this article, it is important to have a nuanced evaluation of how these treatments, which heavily rely on abductive justification, ought to be managed. The just use an abductive approach may be difficult as AI infused precision medicine is further pursued. At baseline, such technology relies on a level of advanced technology literacy among the general public and could exclude populations who lack access to basic technological infrastructure or know-how from participation.[xxxii] Even among nations with adequate infrastructure, as more patients seek out implantable neurotechnologies, which require robust healthcare resources, the market will favor patient populations that can afford this complex care.[xxxiii] If patients already have the means to pay for an initial dose/use of a precision medicine product out of pocket, should insurance providers be required to cover subsequent treatments?[xxxiv] That is, if a first dose of a cancer drug or a deep brain stimulator over its initial battery life is successful, patients may feel justified in having the costs of further treatments covered. The Norwegian patient’s experience implies there is a precedent for the idea that some public insurance companies ought to cover successful cancer therapies, however, insurance companies may not all see themselves as obligated to cover neurotechnologies that rely on personalized settings or that are based on precision/abductive research more than on clinical trials. CONCLUSION The fact that the cases outlined above rely on abductive style of reasoning implies that there may not be as strong a justification for coverage by insurance, as they are both experimental and individualized, when compared to the more traditional large clinical trials in which groups have the same or a standardized protocol (settings/doses). If a study is examining the efficacy of a treatment with a large cohort of patients or with different experimental groups/phases, insurance companies may conclude that the resulting symptom improvements are more likely to be coming from the devices themselves. A preference for inductive justification may take priority when ruling in favor of funding someone’s continued use of an implantable neurostimulator. There are further nuances to this discussion surrounding the classifications of these interventions as research versus clinical care that warrant future exploration, since such a distinction is more of a scale[xxxv] than binary and could have significant impacts on the “right-to-try” approach to experimental therapies in the United States.[xxxvi] Namely, given the inherent limitations of conducting large cohort trials for deep brain stimulation interventions on patients with neuropsychiatric disorders, surgically innovative frameworks that blend abductive and inductive methodologies, like with sham stimulation phases, have traditionally been used.[xxxvii] Similarly, for adaptive brain-computer interface systems, if there are no large clinical trials and instead only publications that demonstrate that something similar worked for someone else, then, in addition to the evidence that the first treatment/dose worked for the patient in question, the balance of reasoning would be valid and arguably justify insurance coverage. As precision approaches to neurotechnology become more common, frameworks for evaluating efficacy will be crucial both for insurance coverage and for clinical decision making. ACKNOWLEDGEMENT This article was originally written as an assignment for Dr. Francis Shen’s “Bioethics & AI” course at Harvard’s Center for Bioethics. I would like to thank Dr. Shen for his comments as well as my colleagues in the Lázaro-Muñoz Lab fo - [i] Jonathan Kimmelman and Ian Tannock, “The Paradox of Precision Medicine,” Nature Reviews. Clinical Oncology 15, no. 6 (June 2018): 341–42, https://doi.org/10.1038/s41571-018-0016-0. [ii] Henrik Vogt and Bjørn Hofmann, “How Precision Medicine Changes Medical Epistemology: A Formative Case from Norway,” Journal of Evaluation in Clinical Practice 28, no. 6 (December 2022): 1205–12, https://doi.org/10.1111/jep.13649. [iii] David Barrett and Ahtisham Younas, “Induction, Deduction and Abduction,” Evidence-Based Nursing 27, no. 1 (January 1, 2024): 6–7, https://doi.org/10.1136/ebnurs-2023-103873. [iv] Vogt and Hofmann, “How Precision Medicine Changes Medical Epistemology,” 1208. [v] Wireko Andrew Awuah et al., “Bridging Minds and Machines: The Recent Advances of Brain-Computer Interfaces in Neurological and Neurosurgical Applications,” World Neurosurgery, May 22, 2024, S1878-8750(24)00867-2, https://doi.org/10.1016/j.wneu.2024.05.104. [vi] Mark Riedl, “A Very Gentle Introduction to Large Language Models without the Hype,” Medium (blog), May 25, 2023, https://mark-riedl.medium.com/a-very-gentle-introduction-to-large-language-models-without-the-hype-5f67941fa59e. [vii] David E. Burdette and Barbara E. Swartz, “Chapter 4 - Responsive Neurostimulation,” in Neurostimulation for Epilepsy, ed. Vikram R. Rao (Academic Press, 2023), 97–132, https://doi.org/10.1016/B978-0-323-91702-5.00002-5. [viii] Kimmelman and Tannock, 2018. [ix] Kimmelman and Tannock, 2018. [x] Simon Lohse, “Mapping Uncertainty in Precision Medicine: A Systematic Scoping Review,” Journal of Evaluation in Clinical Practice 29, no. 3 (April 2023): 554–64, https://doi.org/10.1111/jep.13789. [xi] Kimmelman and Tannock, “The Paradox of Precision Medicine.” [xii] Vogt and Hofmann, 1206. [xiii] Vogt and Hofmann, 1206. [xiv] Vogt and Hofmann, 1206. [xv] Vogt and Hofmann, 1207. [xvi] Vogt and Hofmann, 1207. [xvii] Vogt and Hofmann, 1207. [xviii] Vogt and Hofmann, 1210. [xix] Mehar Sahu et al., “Chapter Three - Artificial Intelligence and Machine Learning in Precision Medicine: A Paradigm Shift in Big Data Analysis,” in Progress in Molecular Biology and Translational Science, ed. David B. Teplow, vol. 190, 1 vols., Precision Medicine (Academic Press, 2022), 57–100, https://doi.org/10.1016/bs.pmbts.2022.03.002. [xx] Stefan Feuerriegel et al., “Causal Machine Learning for Predicting Treatment Outcomes,” Nature Medicine 30, no. 4 (April 2024): 958–68, https://doi.org/10.1038/s41591-024-02902-1. [xxi] Sunderland Baker et al., “Ethical Considerations in Closed Loop Deep Brain Stimulation,” Deep Brain Stimulation 3 (October 1, 2023): 8–15, https://doi.org/10.1016/j.jdbs.2023.11.001. [xxii] David Haslacher et al., “AI for Brain-Computer Interfaces,” 2024, 7, https://doi.org/10.1016/bs.dnb.2024.02.003. [xxiii] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 103–4; “Premarket Approval (PMA),” https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P100026. [xxiv] Burdette and Swartz, “Chapter 4 - Responsive Neurostimulation,” 104. [xxv] Burdette and Swartz, 126. [xxvi] Sean L. Metzger et al., “A High-Performance Neuroprosthesis for Speech Decoding and Avatar Control,” Nature 620, no. 7976 (August 2023): 1037–46, https://doi.org/10.1038/s41586-023-06443-4. [xxvii] Hao Fang and Yuxiao Yang, “Predictive Neuromodulation of Cingulo-Frontal Neural Dynamics in Major Depressive Disorder Using a Brain-Computer Interface System: A Simulation Study,” Frontiers in Computational Neuroscience 17 (March 6, 2023), https://doi.org/10.3389/fncom.2023.1119685; Mahsa Malekmohammadi et al., “Kinematic Adaptive Deep Brain Stimulation for Resting Tremor in Parkinson’s Disease,” Movement Disorders 31, no. 3 (2016): 426–28, https://doi.org/10.1002/mds.26482. [xxviii] Young-Hoon Nho et al., “Responsive Deep Brain Stimulation Guided by Ventral Striatal Electrophysiology of Obsession Durably Ameliorates Compulsion,” Neuron 0, no. 0 (October 20, 2023), https://doi.org/10.1016/j.neuron.2023.09.034. [xxix] Nho et al. [xxx] Nho et al.; Erik Robinson, “Brain Implant at OHSU Successfully Controls Both Seizures and OCD,” OHSU News, accessed March 3, 2024, https://news.ohsu.edu/2023/10/25/brain-implant-at-ohsu-successfully-controls-both-seizures-and-ocd. [xxxi] Awuah et al., “Bridging Minds and Machines”; Haslacher et al., “AI for Brain-Computer Interfaces.” [xxxii] Awuah et al., “Bridging Minds and Machines.” [xxxiii] Sara Green, Barbara Prainsack, and Maya Sabatello, “The Roots of (in)Equity in Precision Medicine: Gaps in the Discourse,” Personalized Medicine 21, no. 1 (January 2024): 5–9, https://doi.org/10.2217/pme-2023-0097. [xxxiv] Green, Prainsack, and Sabatello, 7. [xxxv] Robyn Bluhm and Kirstin Borgerson, “An Epistemic Argument for Research-Practice Integration in Medicine,” The Journal of Medicine and Philosophy: A Forum for Bioethics and Philosophy of Medicine 43, no. 4 (July 9, 2018): 469–84, https://doi.org/10.1093/jmp/jhy009. [xxxvi] Vijay Mahant, “‘Right-to-Try’ Experimental Drugs: An Overview,” Journal of Translational Medicine 18 (June 23, 2020): 253, https://doi.org/10.1186/s12967-020-02427-4. [xxxvii] Michael S. Okun et al., “Deep Brain Stimulation in the Internal Capsule and Nucleus Accumbens Region: Responses Observed during Active and Sham Programming,” Journal of Neurology, Neurosurgery & Psychiatry 78, no. 3 (March 1, 2007): 310–14, https://doi.org/10.1136/jnnp.2006.095315.

When George Orwell encountered ideas of a technological utopia sixty-five years ago, he acted the grumpy middle-aged man Reading recently a batch of rather shallowly optimistic “progressive” books, I was struck by the automatic way in which people go on repeating certain phrases which were fashionable before 1914. Two great favourites are “the abolition of distance” and “the disappearance of frontiers”. I do not know how often I have met with the statements that “the aeroplane and the radio have abolished distance” and “all parts of the world are now interdependent” (1944). It is worth revisiting the old boy’s grumpiness, because the rhetoric he so niftily skewers continues in our own time. Facebook features “Peace on Facebook” and even claims that it can “decrease world conflict” through inter-cultural communication. Twitter has announced itself as “a triumph of humanity” (“A Cyber-House” 61). Queue George. In between Orwell and latter-day hoody cybertarians, a whole host of excitable public intellectuals announced the impending end of materiality through emergent media forms. Marshall McLuhan, Neil Postman, Daniel Bell, Ithiel de Sola Pool, George Gilder, Alvin Toffler—the list of 1960s futurists goes on and on. And this wasn’t just a matter of punditry: the OECD decreed the coming of the “information society” in 1975 and the European Union (EU) followed suit in 1979, while IBM merrily declared an “information age” in 1977. Bell theorized this technological utopia as post-ideological, because class would cease to matter (Mattelart). Polluting industries seemingly no longer represented the dynamic core of industrial capitalism; instead, market dynamism radiated from a networked, intellectual core of creative and informational activities. The new information and knowledge-based economies would rescue First World hegemony from an “insurgent world” that lurked within as well as beyond itself (Schiller). Orwell’s others and the Cold-War futurists propagated one of the most destructive myths shaping both public debate and scholarly studies of the media, culture, and communication. They convinced generations of analysts, activists, and arrivistes that the promises and problems of the media could be understood via metaphors of the environment, and that the media were weightless and virtual. The famous medium they wished us to see as the message —a substance as vital to our wellbeing as air, water, and soil—turned out to be no such thing. Today’s cybertarians inherit their anti-Marxist, anti-materialist positions, as a casual glance at any new media journal, culture-industry magazine, or bourgeois press outlet discloses. The media are undoubtedly important instruments of social cohesion and fragmentation, political power and dissent, democracy and demagoguery, and other fraught extensions of human consciousness. But talk of media systems as equivalent to physical ecosystems—fashionable among marketers and media scholars alike—is predicated on the notion that they are environmentally benign technologies. This has never been true, from the beginnings of print to today’s cloud-covered computing. Our new book Greening the Media focuses on the environmental impact of the media—the myriad ways that media technology consumes, despoils, and wastes natural resources. We introduce ideas, stories, and facts that have been marginal or absent from popular, academic, and professional histories of media technology. Throughout, ecological issues have been at the core of our work and we immodestly think the same should apply to media communications, and cultural studies more generally. We recognize that those fields have contributed valuable research and teaching that address environmental questions. For instance, there is an abundant literature on representations of the environment in cinema, how to communicate environmental messages successfully, and press coverage of climate change. That’s not enough. You may already know that media technologies contain toxic substances. You may have signed an on-line petition protesting the hazardous and oppressive conditions under which workers assemble cell phones and computers. But you may be startled, as we were, by the scale and pervasiveness of these environmental risks. They are present in and around every site where electronic and electric devices are manufactured, used, and thrown away, poisoning humans, animals, vegetation, soil, air and water. We are using the term “media” as a portmanteau word to cover a multitude of cultural and communications machines and processes—print, film, radio, television, information and communications technologies (ICT), and consumer electronics (CE). This is not only for analytical convenience, but because there is increasing overlap between the sectors. CE connect to ICT and vice versa; televisions resemble computers; books are read on telephones; newspapers are written through clouds; and so on. Cultural forms and gadgets that were once separate are now linked. The currently fashionable notion of convergence doesn’t quite capture the vastness of this integration, which includes any object with a circuit board, scores of accessories that plug into it, and a global nexus of labor and environmental inputs and effects that produce and flow from it. In 2007, a combination of ICT/CE and media production accounted for between 2 and 3 percent of all greenhouse gases emitted around the world (“Gartner Estimates,”; International Telecommunication Union; Malmodin et al.). Between twenty and fifty million tonnes of electronic waste (e-waste) are generated annually, much of it via discarded cell phones and computers, which affluent populations throw out regularly in order to buy replacements. (Presumably this fits the narcissism of small differences that distinguishes them from their own past.) E-waste is historically produced in the Global North—Australasia, Western Europe, Japan, and the US—and dumped in the Global South—Latin America, Africa, Eastern Europe, Southern and Southeast Asia, and China. It takes the form of a thousand different, often deadly, materials for each electrical and electronic gadget. This trend is changing as India and China generate their own media detritus (Robinson; Herat). Enclosed hard drives, backlit screens, cathode ray tubes, wiring, capacitors, and heavy metals pose few risks while these materials remain encased. But once discarded and dismantled, ICT/CE have the potential to expose workers and ecosystems to a morass of toxic components. Theoretically, “outmoded” parts could be reused or swapped for newer parts to refurbish devices. But items that are defined as waste undergo further destruction in order to collect remaining parts and valuable metals, such as gold, silver, copper, and rare-earth elements. This process causes serious health risks to bones, brains, stomachs, lungs, and other vital organs, in addition to birth defects and disrupted biological development in children. Medical catastrophes can result from lead, cadmium, mercury, other heavy metals, poisonous fumes emitted in search of precious metals, and such carcinogenic compounds as polychlorinated biphenyls, dioxin, polyvinyl chloride, and flame retardants (Maxwell and Miller 13). The United States’ Environmental Protection Agency estimates that by 2007 US residents owned approximately three billion electronic devices, with an annual turnover rate of 400 million units, and well over half such purchases made by women. Overall CE ownership varied with age—adults under 45 typically boasted four gadgets; those over 65 made do with one. The Consumer Electronics Association (CEA) says US$145 billion was expended in the sector in 2006 in the US alone, up 13% on the previous year. The CEA refers joyously to a “consumer love affair with technology continuing at a healthy clip.” In the midst of a recession, 2009 saw $165 billion in sales, and households owned between fifteen and twenty-four gadgets on average. By 2010, US$233 billion was spent on electronic products, three-quarters of the population owned a computer, nearly half of all US adults owned an MP3 player, and 85% had a cell phone. By all measures, the amount of ICT/CE on the planet is staggering. As investigative science journalist, Elizabeth Grossman put it: “no industry pushes products into the global market on the scale that high-tech electronics does” (Maxwell and Miller 2). In 2007, “of the 2.25 million tons of TVs, cell phones and computer products ready for end-of-life management, 18% (414,000 tons) was collected for recycling and 82% (1.84 million tons) was disposed of, primarily in landfill” (Environmental Protection Agency 1). Twenty million computers fell obsolete across the US in 1998, and the rate was 130,000 a day by 2005. It has been estimated that the five hundred million personal computers discarded in the US between 1997 and 2007 contained 6.32 billion pounds of plastics, 1.58 billion pounds of lead, three million pounds of cadmium, 1.9 million pounds of chromium, and 632000 pounds of mercury (Environmental Protection Agency; Basel Action Network and Silicon Valley Toxics Coalition 6). The European Union is expected to generate upwards of twelve million tons annually by 2020 (Commission of the European Communities 17). While refrigerators and dangerous refrigerants account for the bulk of EU e-waste, about 44% of the most toxic e-waste measured in 2005 came from medium-to-small ICT/CE: computer monitors, TVs, printers, ink cartridges, telecommunications equipment, toys, tools, and anything with a circuit board (Commission of the European Communities 31-34). Understanding the enormity of the environmental problems caused by making, using, and disposing of media technologies should arrest our enthusiasm for them. But intellectual correctives to the “love affair” with technology, or technophilia, have come and gone without establishing much of a foothold against the breathtaking flood of gadgets and the propaganda that proclaims their awe-inspiring capabilities.[i] There is a peculiar enchantment with the seeming magic of wireless communication, touch-screen phones and tablets, flat-screen high-definition televisions, 3-D IMAX cinema, mobile computing, and so on—a totemic, quasi-sacred power that the historian of technology David Nye has named the technological sublime (Nye Technological Sublime 297).[ii] We demonstrate in our book why there is no place for the technological sublime in projects to green the media. But first we should explain why such symbolic power does not accrue to more mundane technologies; after all, for the time-strapped cook, a pressure cooker does truly magical things. Three important qualities endow ICT/CE with unique symbolic potency—virtuality, volume, and novelty. The technological sublime of media technology is reinforced by the “virtual nature of much of the industry’s content,” which “tends to obscure their responsibility for a vast proliferation of hardware, all with high levels of built-in obsolescence and decreasing levels of efficiency” (Boyce and Lewis 5). Planned obsolescence entered the lexicon as a new “ethics” for electrical engineering in the 1920s and ’30s, when marketers, eager to “habituate people to buying new products,” called for designs to become quickly obsolete “in efficiency, economy, style, or taste” (Grossman 7-8).[iii] This defines the short lifespan deliberately constructed for computer systems (drives, interfaces, operating systems, batteries, etc.) by making tiny improvements incompatible with existing hardware (Science and Technology Council of the American Academy of Motion Picture Arts and Sciences 33-50; Boyce and Lewis). With planned obsolescence leading to “dizzying new heights” of product replacement (Rogers 202), there is an overstated sense of the novelty and preeminence of “new” media—a “cult of the present” is particularly dazzled by the spread of electronic gadgets through globalization (Mattelart and Constantinou 22). References to the symbolic power of media technology can be found in hymnals across the internet and the halls of academe: technologies change us, the media will solve social problems or create new ones, ICTs transform work, monopoly ownership no longer matters, journalism is dead, social networking enables social revolution, and the media deliver a cleaner, post-industrial, capitalism. Here is a typical example from the twilight zone of the technological sublime (actually, the OECD): A major feature of the knowledge-based economy is the impact that ICTs have had on industrial structure, with a rapid growth of services and a relative decline of manufacturing. Services are typically less energy intensive and less polluting, so among those countries with a high and increasing share of services, we often see a declining energy intensity of production … with the emergence of the Knowledge Economy ending the old linear relationship between output and energy use (i.e. partially de-coupling growth and energy use) (Houghton 1) This statement mixes half-truths and nonsense. In reality, old-time, toxic manufacturing has moved to the Global South, where it is ascendant; pollution levels are rising worldwide; and energy consumption is accelerating in residential and institutional sectors, due almost entirely to ICT/CE usage, despite advances in energy conservation technology (a neat instance of the age-old Jevons Paradox). In our book we show how these are all outcomes of growth in ICT/CE, the foundation of the so-called knowledge-based economy. ICT/CE are misleadingly presented as having little or no material ecological impact. In the realm of everyday life, the sublime experience of electronic machinery conceals the physical work and material resources that go into them, while the technological sublime makes the idea that more-is-better palatable, axiomatic; even sexy. In this sense, the technological sublime relates to what Marx called “the Fetishism which attaches itself to the products of labour” once they are in the hands of the consumer, who lusts after them as if they were “independent beings” (77). There is a direct but unseen relationship between technology’s symbolic power and the scale of its environmental impact, which the economist Juliet Schor refers to as a “materiality paradox” —the greater the frenzy to buy goods for their transcendent or nonmaterial cultural meaning, the greater the use of material resources (40-41). We wrote Greening the Media knowing that a study of the media’s effect on the environment must work especially hard to break the enchantment that inflames popular and elite passions for media technologies. We understand that the mere mention of the political-economic arrangements that make shiny gadgets possible, or the environmental consequences of their appearance and disappearance, is bad medicine. It’s an unwelcome buzz kill—not a cool way to converse about cool stuff. But we didn’t write the book expecting to win many allies among high-tech enthusiasts and ICT/CE industry leaders. We do not dispute the importance of information and communication media in our lives and modern social systems. We are media people by profession and personal choice, and deeply immersed in the study and use of emerging media technologies. But we think it’s time for a balanced assessment with less hype and more practical understanding of the relationship of media technologies to the biosphere they inhabit. Media consumers, designers, producers, activists, researchers, and policy makers must find new and effective ways to move ICT/CE production and consumption toward ecologically sound practices. In the course of this project, we found in casual conversation, lecture halls, classroom discussions, and correspondence, consistent and increasing concern with the environmental impact of media technology, especially the deleterious effects of e-waste toxins on workers, air, water, and soil. We have learned that the grip of the technological sublime is not ironclad. Its instability provides a point of departure for investigating and criticizing the relationship between the media and the environment. The media are, and have been for a long time, intimate environmental participants. Media technologies are yesterday’s, today’s, and tomorrow’s news, but rarely in the way they should be. The prevailing myth is that the printing press, telegraph, phonograph, photograph, cinema, telephone, wireless radio, television, and internet changed the world without changing the Earth. In reality, each technology has emerged by despoiling ecosystems and exposing workers to harmful environments, a truth obscured by symbolic power and the power of moguls to set the terms by which such technologies are designed and deployed. Those who benefit from ideas of growth, progress, and convergence, who profit from high-tech innovation, monopoly, and state collusion—the military-industrial-entertainment-academic complex and multinational commandants of labor—have for too long ripped off the Earth and workers. As the current celebration of media technology inevitably winds down, perhaps it will become easier to comprehend that digital wonders come at the expense of employees and ecosystems. This will return us to Max Weber’s insistence that we understand technology in a mundane way as a “mode of processing material goods” (27). Further to understanding that ordinariness, we can turn to the pioneering conversation analyst Harvey Sacks, who noted three decades ago “the failures of technocratic dreams [:] that if only we introduced some fantastic new communication machine the world will be transformed.” Such fantasies derived from the very banality of these introductions—that every time they took place, one more “technical apparatus” was simply “being made at home with the rest of our world’ (548). Media studies can join in this repetitive banality. Or it can withdraw the welcome mat for media technologies that despoil the Earth and wreck the lives of those who make them. In our view, it’s time to green the media by greening media studies. References “A Cyber-House Divided.” Economist 4 Sep. 2010: 61-62. “Gartner Estimates ICT Industry Accounts for 2 Percent of Global CO2 Emissions.” Gartner press release. 6 April 2007. ‹http://www.gartner.com/it/page.jsp?id=503867›. Basel Action Network and Silicon Valley Toxics Coalition. Exporting Harm: The High-Tech Trashing of Asia. Seattle: Basel Action Network, 25 Feb. 2002. Benjamin, Walter. “Central Park.” Trans. Lloyd Spencer with Mark Harrington. New German Critique 34 (1985): 32-58. Biagioli, Mario. “Postdisciplinary Liaisons: Science Studies and the Humanities.” Critical Inquiry 35.4 (2009): 816-33. Boyce, Tammy and Justin Lewis, eds. Climate Change and the Media. New York: Peter Lang, 2009. Commission of the European Communities. “Impact Assessment.” Commission Staff Working Paper accompanying the Proposal for a Directive of the European Parliament and of the Council on Waste Electrical and Electronic Equipment (WEEE) (recast). COM (2008) 810 Final. Brussels: Commission of the European Communities, 3 Dec. 2008. Environmental Protection Agency. Management of Electronic Waste in the United States. Washington, DC: EPA, 2007 Environmental Protection Agency. Statistics on the Management of Used and End-of-Life Electronics. Washington, DC: EPA, 2008 Grossman, Elizabeth. Tackling High-Tech Trash: The E-Waste Explosion & What We Can Do about It. New York: Demos, 2008. ‹http://www.demos.org/pubs/e-waste_FINAL.pdf› Herat, Sunil. “Review: Sustainable Management of Electronic Waste (e-Waste).” Clean 35.4 (2007): 305-10. Houghton, J. “ICT and the Environment in Developing Countries: Opportunities and Developments.” Paper prepared for the Organization for Economic Cooperation and Development, 2009. International Telecommunication Union. ICTs for Environment: Guidelines for Developing Countries, with a Focus on Climate Change. Geneva: ICT Applications and Cybersecurity Division Policies and Strategies Department ITU Telecommunication Development Sector, 2008. Malmodin, Jens, Åsa Moberg, Dag Lundén, Göran Finnveden, and Nina Lövehagen. “Greenhouse Gas Emissions and Operational Electricity Use in the ICT and Entertainment & Media Sectors.” Journal of Industrial Ecology 14.5 (2010): 770-90. Marx, Karl. Capital: Vol. 1: A Critical Analysis of Capitalist Production, 3rd ed. Trans. Samuel Moore and Edward Aveling, Ed. Frederick Engels. New York: International Publishers, 1987. Mattelart, Armand and Costas M. Constantinou. “Communications/Excommunications: An Interview with Armand Mattelart.” Trans. Amandine Bled, Jacques Guot, and Costas Constantinou. Review of International Studies 34.1 (2008): 21-42. Mattelart, Armand. “Cómo nació el mito de Internet.” Trans. Yanina Guthman. El mito internet. Ed. Victor Hugo de la Fuente. Santiago: Editorial aún creemos en los sueños, 2002. 25-32. Maxwell, Richard and Toby Miller. Greening the Media. New York: Oxford University Press, 2012. Nye, David E. American Technological Sublime. Cambridge, Mass.: MIT Press, 1994. Nye, David E. Technology Matters: Questions to Live With. Cambridge, Mass.: MIT Press. 2007. Orwell, George. “As I Please.” Tribune. 12 May 1944. Richtel, Matt. “Consumers Hold on to Products Longer.” New York Times: B1, 26 Feb. 2011. Robinson, Brett H. “E-Waste: An Assessment of Global Production and Environmental Impacts.” Science of the Total Environment 408.2 (2009): 183-91. Rogers, Heather. Gone Tomorrow: The Hidden Life of Garbage. New York: New Press, 2005. Sacks, Harvey. Lectures on Conversation. Vols. I and II. Ed. Gail Jefferson. Malden: Blackwell, 1995. Schiller, Herbert I. Information and the Crisis Economy. Norwood: Ablex Publishing, 1984. Schor, Juliet B. Plenitude: The New Economics of True Wealth. New York: Penguin, 2010. Science and Technology Council of the American Academy of Motion Picture Arts and Sciences. The Digital Dilemma: Strategic Issues in Archiving and Accessing Digital Motion Picture Materials. Los Angeles: Academy Imprints, 2007. Weber, Max. “Remarks on Technology and Culture.” Trans. Beatrix Zumsteg and Thomas M. Kemple. Ed. Thomas M. Kemple. Theory, Culture [i] The global recession that began in 2007 has been the main reason for some declines in Global North energy consumption, slower turnover in gadget upgrades, and longer periods of consumer maintenance of electronic goods (Richtel). [ii] The emergence of the technological sublime has been attributed to the Western triumphs in the post-Second World War period, when technological power supposedly supplanted the power of nature to inspire fear and astonishment (Nye Technology Matters 28). Historian Mario Biagioli explains how the sublime permeates everyday life through technoscience: "If around 1950 the popular imaginary placed science close to the military and away from the home, today’s technoscience frames our everyday life at all levels, down to our notion of the self" (818). [iii] This compulsory repetition is seemingly undertaken each time as a novelty, governed by what German cultural critic Walter Benjamin called, in his awkward but occasionally illuminating prose, "the ever-always-the-same" of "mass-production" cloaked in "a hitherto unheard-of significance" (48).

Michael Haneke’s film Caché tells the story of a bourgeois family in peril. The comfortable lives of the Laurents—husband Georges (Daniel Auteuil), wife Anne (Juliette Binoche), and teenage son Pierrot (Lester Makedonsky)—are disrupted when surveillance tapes of their home and private conversations are delivered to them anonymously. Ostensibly Caché sits in a familiar generic framework: the thriller narrative of a family under threat is reminiscent of films such as The Desperate Hours (1955), Cape Fear (1962), and Straw Dogs (1971). The weight of outside forces causes tension within the family dynamic and Georges spends much of the film playing detective (unravelling clues from the tapes and from his past). This framing draws us in; it is presumed that the mystery of the family’s harassment will finally be solved, and yet Haneke’s treatment of this material undermines viewer expectations. This paper examines the process of suspicious reading when applied to a film that encourages such a method, only to thwart the viewer’s attempts to come to a definitive meaning. I argue that Caché plays with generic expectations in order to critique the interpretive process, and consider what implications this has for suspicious readers. Caché positions us as detective. Throughout the film we follow Georges’s investigation to unravel the film’s central enigma: Who is sending the tapes? The answer to this, however, is never revealed. Instead viewers are left with more questions than answers; it seems that for every explanation there is a circumventing intricacy. This lack of narrative closure within the surface framework of a psychological thriller has proven fertile ground for critics, scholars, and home viewers alike as they painstakingly try to ascertain the elusive culprit. Character motives are scrutinised, performances are analysed, specific shots are dissected, and various theories have been canvassed. The viewer becomes ensnared in the hermeneutics of suspicion, a critical reading strategy that literary theorist Rita Felski has compared to the hard-boiled crime story, a scenario in which critic becomes detective, and text becomes criminal suspect to be “scrutinized, interrogated, and made to yield its hidden secrets” (224). Like Georges, the viewer becomes investigator, sifting through the available evidence in the vain hope that with scrupulous attention the film will surrender its mystery.Of course, Haneke is not unique in his withholding of a film’s enigma. David Lynch’s surreal neo-noir Lost Highway (1997) and Mulholland Drive (2001) have garnered a similar response and continue to be debated. Film scholar Mark Cousins compares Caché’s reception at Cannes to other landmark film and television examples:Where Dallas made people ask ‘who?’, Twin Peaks ‘what?’, the genre-bending films of the last decade ‘how?’ and The Crying Game was about the implications of the answer, Caché’s conversational buzz was more circular. Yes, we asked ‘who?’ Then, when it was clear this question was not answered by the film, we considered why it was not answered. (225–6)Felski’s meditation on the hermeneutics of suspicion touches on this issue, considering literary texts as preemptive of our mistrust. Extending Felski’s reasoning here as applicable to other forms of cultural expression, I would like to argue that Caché is a film that “matches and exceeds the critic’s own vigilance” for it is already involved in “subverting the self-evident, challenging the commonplace, [and] relentlessly questioning idées fixes and idées recus” (Felski 217). Caché challenges fixed and received ideas pertaining to audience expectations of the thriller film, subverting generic conventions that traditionally see the enigma resolved, the culprit apprehended, and order restored. More than simply refusing closure, Caché casts doubt on the very clues it offers up as evidence. Such a text performs “a meta-commentary on the traps of interpretation, a knowing anticipation and exposure of all possible hermeneutic blunders” (Felski 217). Throughout her essay, Felski highlights the lures and pitfalls of suspicious reading practices. Felski warns that attempts to gain mastery over texts by drawing to light purportedly obscured meanings are often as concerned with self-congratulatory demonstrations of skill in drawing hitherto unmade connections as they are with the texts themselves (230). While I do not wish to endorse suspicious reading as an unproblematic approach, the present paper considers what happens when readers encounter a text that seemingly cannot be approached in any other way. Unlike the realist literary narratives and mystery stories drawn on by Felski, Caché resists a manifest meaning in both form and content, making it nearly impossible for viewers not to search for latent meaning.So where are suspicious readers left when the texts interrogated refuse to bend to the demands placed on them? This is the question I will be examining in the remainder of this paper through the questions Caché poses and the care it takes in ensuring its enigmatic quality. I will proceed by breaking down what I believe to be the three possible avenues of response—Caché as impossible puzzle, inconclusive puzzle, or wrong puzzle—and their implications.I The Impossible Puzzle Caché opens with a static frame long take of a Parisian residential street. This could be mistaken for a still image until a pedestrian bustles past. A woman leaves her house centre frame. A cyclist turns the corner. “Well?” a male voice intones. “Nothing,” a female replies. The voices come from off-screen, and soon after the image is interrupted by fast forward lines, revealing that what we have been watching is not an image of the present moment but a video cassette of time already elapsed; the voices belong to our protagonists, Georges and Anne, commenting on its content and manipulating its playback. From the opening moments it becomes clear that we cannot be certain of what we are seeing or when we are seeing it.This presents an intriguing tension between form and content that complicates our attempts to gather evidence. Haneke pares back style in a manner reminiscent of the films of Robert Bresson or the work of the Italian neo-realists. Caché’s long takes, naturalistic lighting, and emphasis on the everyday suggest a realist aesthetic; the viewer can invest faith in these images because they ascribe to a familiar paradigm, one in which artifice is apparently minimal. This notion that a realist aesthetic equates to straightforward images is at odds, however, with both the thriller narrative (in which solutions must be concealed before they can be uncovered) and Haneke’s constant undermining of the ontology of the image; throughout the film, viewers will be disoriented by Haneke’s manipulation of time and space with unclear or retroactive distinctions between past, present, video, dream, memory, and reality.An additional contention might be the seemingly impossible placement of the hidden camera. In the same tape, Georges leaves the house and walks towards the camera, unaware of it. The shot indicates the camera must be elevated in the street, and at one point it appears that Georges is looking right at it. A later recording takes place in the apartment of Georges’s suspect, Majid. Viewers are given ample opportunity to scour the mise en scène to find what apparently is not there. Perhaps the camera is just too well hidden. But if this is not the case and we can neither locate nor conceive of the camera’s placement because it simply cannot be there, this would seem to break the rules of the game. If we are to formulate theories as to the culprit at large, what good is our evidence if it is unreliable? Viewers could stop here and conclude that a puzzle without a solution amounts to a film without a point. “Well?” Georges asks in the film’s opening. “Nothing,” Anne replies. Case closed. Short of giving up on a solution, one might conclude (as Antoine Doinel has) that those looking within the film for a perpetrator are looking in the wrong place. When the motives or opportunities of on-screen characters do not add up, perhaps it is Haneke one should turn to. Those familiar with Haneke’s earlier film Funny Games (1997) will know he is not afraid to break the tacit rules by which we suspend our disbelief if there is a point to be made. Film scholar David Sorfa concludes it is in fact the audience who send the tapes; Caché’s narrative is fuelled by the desire of viewers who want to see a film (102). Tempting though these solutions might be (Georges does not see the camera because he is a fictional character in a film unaware of its creator), as critic Roger Ebert has pointed out, such theories render both the film’s content, and any analysis of it, without purpose: It introduces a wild card. It essentially means that no analysis of the film is relevant, because nothing need make sense and no character actions need be significant. Therefore, the film would have the appearance of a whodunit but with no who and no dunnit. (“Caché: A Riddle”)The Caché as impossible puzzle avenue leaves the suspicious reader without reason to engage. If there can be no reward for our efforts, we are left without incentive. Alternately, if we conclude that Haneke is but the puppet master sadistically toying with his characters, we are left at a similar juncture; our critical enquiry has all the consequence of the trite “but it was all a dream…” scenario. “Well?” “Nothing.” I suspect there is more to Caché than that. A film so explicit in its stimulation of suspicious reading seems to merit our engagement. However, this is not to say that our attention will be satisfied with the neatly tied up solution we might expect. II The Inconclusive Puzzle When, one evening, Pierrot does not come home as expected, Georges and Anne conclude the boy has been kidnapped. They interpret their son’s absence as an escalation in the “campaign of terror” that had hitherto consisted of surveillance videos, odd phone calls, and childlike but portent drawings. With police assistance, Georges goes to confront his suspect, Majid. An Algerian boy from his childhood, now middle aged and disadvantaged because of lies Georges told as a child, Majid has already (quite convincingly) denied any knowledge of the tapes. At the door they meet Majid’s son who is equally perplexed at the accusation of kidnapping. The pair are arrested and an exhausted Georges returns home to explain the situation to his wife:Georges: So now they’re both in the cage for the night.Anne: And then?Georges: Then they’ll let them go. If there’s no proof, they have to. There’s suspicion, nothing more.The next day a sullen Pierrot returns home, having stayed the night at a friend’s without notifying his parents. His clear disdain for his mother is revealed as he rejects her affection and accuses her of having an affair. Pierrot likewise treats his father with disinterest, raising viewer suspicion that he might have a motive for tormenting his parents with the videotapes. Pierrot is just one cog in the family’s internal mechanism of suspicion, however. Whether or not Anne is actually having an affair can only be speculated; she denies it, but other scenes open the way to our suspicion. Anne is rightly suspicious of Georges’s reluctance to be open about his past as his proclivity to lie is gradually revealed. In short, Haneke deliberately layers the film with complexity and ambiguity; numerous characters could be implicated, and many questions are raised but few are answered.This suggests that suspicious readers might have recourse to Haneke as author of the text. Haneke, however, celebrates Caché’s ambiguity and his decision to leave the film open: “The truth is always hidden…that’s how it is in the real world. We never, ever know what the truth is. There are a thousand versions of the truth. It depends on your point of view” (Haneke). In interview, Haneke’s language also raises suspicion. At times he speaks knowingly (refusing to reveal important dialogue that occurs in the film’s final shot—an extreme long shot, the characters too distant to be heard), and at other times he seems as uncertain as his viewers (commenting on Anne’s denial of an affair, Haneke remarks “I believe her because she plays it very seriously. But you never know”) (Haneke).Despite this reluctance to offer explanations, Haneke’s status as an auteur with recurring concerns and an ever-developing vision prompts suspicious readers to evaluate Caché in light of his greater oeuvre. Those suspecting Pierrot of wanting to punish his parents might find their theory bolstered by Benny’s Video (1992), Haneke’s film about a teenage boy who murders a friend and then turns in his parents to the police for helping him cover it up. Furthermore, Das Weiße Band (The White Ribbon, 2009) is set in a small German village on the eve of World War One and the narrative strongly suggests the town’s children are responsible for a series of malicious crimes. Whilst malign children in Haneke’s other works cannot explain Caché’s mystery, his oeuvre provides a greater context in which to consider the film, and regenerates discussion as viewers look for patterns in the subject matter Haneke chooses to explore. Regarding Caché as an inconclusive puzzle shifts the emphasis from a neatly packaged solution to a renewable process of discovery. To suggest that there is an answer to be found in the text, a culprit who escapes apprehension but is at least present to be caught, gives suspicious readers cause to engage and re-engage. It is to assume that the film is not without a point. Close attention may reward us with meaningful nuances that colour our interpretation. Haneke’s obsessive attention to detail also seems to suggest that nothing on screen is accidental or arbitrary, that our concentration is warranted, and that active viewing is a necessity even if our expectations and desires for closure may not be granted.Caché ends without revealing its secret. Georges’s suspect Majid has committed suicide (perhaps due to the trauma dredged up by Georges’s accusations), Majid’s son has confronted Georges at his work place (“I wondered how it feels, a man’s life on your conscience?”), and Georges has refused any responsibility for his actions in the distant and recent past. Of the film’s conclusion, cinema theorist Martine Beugnet writes:In the end […] we watch him draw the curtains, take a sleeping pill and go to bed: an emphatic way of signifying the closure of an episode, the return to normality—the conclusion of the film. Yet the images ‘refuse’ to comply: behind the closing credits, the questioning gaze not only persists but affirms its capacity to reinvent itself. (230)The images Beugnet is referring to are the two final shots, which are both static long takes. The first is an extreme long shot, taken from the darkness of a barn into the bright courtyard of the family estate of Georges’s childhood. A child (Majid) is forcibly removed from the home and taken away in a car (presumably to an orphanage due to the lies told by a jealous Georges). This shot is followed by the film’s closing shot, another extreme long shot, this time of the front steps of Pierrot’s school. The frame is cluttered with children and parents, and our eyes are not directed anywhere in particular. Some viewers will notice Pierrot chatting with Majid’s son (a potentially revealing conversation that cannot be heard), others will not see the two young men hidden in the crowd. Eventually the credits roll over this image.Georges’s attempts to shut out the world seem undermined by these images, as Beugnet writes they “‘refuse’ to comply” to this notion of conclusion. Instead of bringing closure to the narrative, they raise more questions. What and when are they? One cannot be sure. The first shot may be a dream or a memory; its placement after a shot of Georges going to bed might encourage us to connect the two. The second shot at the school could be more surveillance footage, or possibly another dream. It might imply the boys have conspired together. It might imply Majid’s son is confronting Pierrot with information about his father. It could be interpreted as the end of the narrative, but it could also be the beginning. Some read it as threatening, others as hopeful. It might imply so many things. However, this “questioning gaze” that persists and reinvents itself is not just the gaze of the film. It is also the gaze of the suspicious reader. From the initial hype upon the film’s Cannes release in 2005, to the various theories circulating in online forums, to Ebert’s scrupulous re-evaluation of the film’s enigma in 2010, to the ever developing body of scholarly work on Haneke’s films, it seems Caché’s mileage for suspicious readers is still running strong, not least because “whodunit?” may be the wrong question.III The Wrong PuzzleOliver C. Speck has remarked that Caché is “Haneke’s most accessible film, but also the most densely layered,” leading the viewer “on a search for clues that always ends in frustration” (97). For Ebert, the film’s lack of resolution leaves the viewer “feeling as the characters feel, uneasy, violated, spied upon, surrounded by faceless observers” (“Caché”). Cousins likewise comments on the process Caché instigates: The film structures our experience in a generically gripping way but then the structure melts away at the moment when it should most cohere, requiring us to look back along its length (the structure’s length and the film’s) to work out where we went wrong. But we did not go wrong. We went where we were told to go, we took the hand of the narrative that, in the final stages, slipped away, leaving us without co-ordinates. (226)The "whodunit” of Caché cannot be definitively proven. Ultimately, viewers can have suspicion, nothing more. So where are we left as suspicious readers when texts such as Caché surpass our own critical vigilance? We can throw in the towel and claim that an impossible puzzle does not deserve our efforts. We can accept that the text has out-played us; it is an inconclusive but compelling puzzle that does not provide enough links in the hermeneutic chain for us to find the closure we seek. Alternately, when the answer is not forthcoming, we can hypothesise that perhaps we have been asking the wrong question; whodunit is beside the point, simply a Hitchcockian MacGuffin (the object or objective that the protagonists seek) introduced to bait us into confronting much more important questions. Perhaps instead we should be asking what Caché can tell us about colonial histories, guilt, vision, or the ontology of cinema itself.This is the avenue many scholars have taken, and the avenue Haneke (rather than his film necessarily) would have us take. The “who did what, when, why, and how” might be regarded as beside the point. In an interview with Andrew O’Hehir, Haneke is quoted:These superficial questions are the glue that holds the spectator in place, and they allow me to raise underlying questions that they have to grapple with. It’s relatively unimportant who sent the tapes, but by engaging with that the viewer must engage questions that are far less banal.Catherine Wheatley agrees, arguing Caché’s open ending renders the epistemological questions of the guilty party and their motives irrelevant, giving preference to questions raised by how this chain of events affect Georges, and by extension the viewer (163–4). By refusing to divulge its secrets, Caché both incites and critiques the interpretive process, encouraging us to take up the role of detective only to anticipate and exceed our investigative efforts. Caché’s subversion of the self-evident is as much a means to launch its thriller narrative as it is a way of calling into question our very understanding of what “self-evident” means. Where Felski describes suspicious interpretations of realist texts (those that attempt to unmask the ideologies concealed behind an illusion of transparency and totality), from its opening moments, Caché is already and constantly unmasking itself. The film’s resistance of a superficial reading seems to make suspicious interpretation inevitable. Wherever viewer suspicion is directed, however, it relies on engagement. Without reason to engage, viewers are left with an impossible puzzle where critical involvement and attention is of no consequence. “Who is sending the tapes?” may be an unimportant or unanswerable question, but it must always be a valid one. It is this query that incites and fuels the interpretive process. As there can only ever be suspicion, nothing more, perhaps it is the question rather than “the answer” that is of utmost significance.Works CitedBeugnet, Martine. “Blind Spot.” Screen 48.2 (2007): 227–31.Benny’s Video. Dir. Michael Haneke. Madman, 1992.Caché (Hidden). Dir. Michael Haneke. Sony Pictures Classics, 2005. Cape Fear. Dir. J. Lee Thompson. Universal, 1962.Cousins, Mark. “After the End: Word of Mouth and Caché.” Screen 48.2 (2007): 223–6.Desperate Hours, The. Dir. William Wyler. Paramount, 1955.Doinel, Antoine. “(Un)hidden Camera: The ‘Real’ Sender of the Tapes.” Mubi.com. Mubi. n.d. 10 Apr. 2011. ‹http://mubi.com/topics/461›. Ebert, Roger. “Caché.” Roger Ebert.com. Chicago Sun-Times. 13 Jan. 2006. 25 Feb. 2011. ‹http://rogerebert.suntimes.com/apps/pbcs.dll/article?AID=/20060112/REVIEWS/51220007›.---. “Caché: A Riddle, Wrapped in a Mystery, Inside an Enigma [Response to Readers].” Roger Ebert’s Journal. Chicago Sun-Times. 18 Jan. 2010. 2 Apr. 2011. ‹http://blogs.suntimes.com/ebert/2010/01/a_riddle_wrapped_in_a_mystery.html›.Felski, Rita. “Suspicious Minds.” Poetics Today 32.2 (2011): 215–34.Funny Games. Dir. Michael Haneke. Madman, 1997.Haneke, Michael. “Hidden: Interview with Michael Haneke by Serge Toubiana.” DVD Special Features. Hidden (Caché). Dir. Michael Haneke. Madman, 2005.Lost Highway. Dir. David Lynch. Universal, 1997.Mulholland Drive. Dir. David Lynch. Reel, 2001.O’Hehir, Andrew. “Michael Haneke’s ‘White Ribbon.’” Salon.com. Salon. 2 Jan. 2010. 2 Apr. 2011. ‹http://www.salon.com/entertainment/movies/andrew_ohehir/2010/01/02/haneke›.Sorfa, David. “Uneasy Domesticity in the Films of Michael Haneke.” Studies in European Cinema 3.2 (2006): 93–104.Speck, Oliver C. Funny Frames: The Filmic Concepts of Michael Haneke. New York: Continuum, 2010.Straw Dogs. Dir. Sam Peckinpah. MRA, 1971.Wheatley, Catherine. Michael Haneke’s Cinema: The Ethic of the Image. New York: Berghahn Books, 2009.White Ribbon, The (Das Weiße Band). Dir. Michael Haneke. Artificial Eye, 2009.

Since the first days of the World Wide Web, artists like myself have been exploring the new possibilities of network interactivity. Some good tools and languages have been developed and made available free for the public to use. This has empowered individuals to participate in the media in ways that are quite remarkable. Nonetheless, the future of independent media is clouded by legal, regulatory, and organisational challenges that need to be addressed. It is not clear to what extent independent content producers will be able to build upon the successes of the 90s – it is yet to be seen whether their efforts will be largely nullified by the anticyclones of a hostile media market. Not so long ago, American news magazines were covering the Browser War. Several real wars later, the terms of surrender are becoming clearer. Now both of the major Internet browsers are owned by huge media corporations, and most of the states (and Reagan-appointed judges) that were demanding the break-up of Microsoft have given up. A curious about-face occurred in U.S. Justice Department policy when John Ashcroft decided to drop the federal case. Maybe Microsoft's value as a partner in covert activity appealed to Ashcroft more than free competition. Regardless, Microsoft is now turning its wrath on new competitors, people who are doing something very, very bad: sharing the products of their own labour. This practice of sharing source code and building free software infrastructure is epitomised by the continuing development of Linux. Everything in the Linux kernel is free, publicly accessible information. As a rule, the people building this "open source" operating system software believe that maintaining transparency is important. But U.S. courts are not doing much to help. In a case brought by the Motion Picture Association of America against Eric Corley, a federal district court blocked the distribution of source code that enables these systems to play DVDs. In addition to censoring Corley's journal, the court ruled that any programmer who writes a program that plays a DVD must comply with a host of license restrictions. In short, an established and popular media format (the DVD) cannot be used under open source operating systems without sacrificing the principle that software source code should remain in the public domain. Should the contents of operating systems be tightly guarded secrets, or subject to public review? If there are capable programmers willing to create good, free operating systems, should the law stand in their way? The question concerning what type of software infrastructure will dominate personal computers in the future is being answered as much by disappointing legal decisions as it is by consumer choice. Rather than ensuring the necessary conditions for innovation and cooperation, the courts permit a monopoly to continue. Rather than endorsing transparency, secrecy prevails. Rather than aiming to preserve a balance between the commercial economy and the gift-economy, sharing is being undermined by the law. Part of the mystery of the Internet for a lot of newcomers must be that it seems to disprove the old adage that you can't get something for nothing. Free games, free music, free pornography, free art. Media corporations are doing their best to change this situation. The FBI and trade groups have blitzed the American news media with alarmist reports about how children don't understand that sharing digital information is a crime. Teacher Gail Chmura, the star of one such media campaign, says of her students, "It's always been interesting that they don't see a connection between the two. They just don't get it" (Hopper). Perhaps the confusion arises because the kids do understand that digital duplication lets two people have the same thing. Theft is at best a metaphor for the copying of data, because the original is not stolen in the same sense as a material object. In the effort to liken all copying to theft, legal provisions for the fair use of intellectual property are neglected. Teachers could just as easily emphasise the importance of sharing and the development of an electronic commons that is free for all to use. The values advanced by the trade groups are not beyond question and are not historical constants. According to Donald Krueckeberg, Rutgers University Professor of Urban Planning, native Americans tied the concept of property not to ownership but to use. "One used it, one moved on, and use was shared with others" (qtd. in Batt). Perhaps it is necessary for individuals to have dominion over some private data. But who owns the land, wind, sun, and sky of the Internet – the infrastructure? Given that publicly-funded research and free software have been as important to the development of the Internet as have business and commercial software, it is not surprising that some ambiguity remains about the property status of the dataverse. For many the Internet is as much a medium for expression and the interplay of languages as it is a framework for monetary transaction. In the case involving DVD software mentioned previously, there emerged a grass-roots campaign in opposition to censorship. Dozens of philosophical programmers and computer scientists asserted the expressive and linguistic bases of software by creating variations on the algorithm needed to play DVDs. The forbidden lines of symbols were printed on T-shirts, translated into different computer languages, translated into legal rhetoric, and even embedded into DNA and pictures of MPAA president Jack Valenti (see e.g. Touretzky). These efforts were inspired by a shared conviction that important liberties were at stake. Supporting the MPAA's position would do more than protect movies from piracy. The use of the algorithm was not clearly linked to an intent to pirate movies. Many felt that outlawing the DVD algorithm, which had been experimentally developed by a Norwegian teenager, represented a suppression of gumption and ingenuity. The court's decision rejected established principles of fair use, denied the established legality of reverse engineering software to achieve compatibility, and asserted that journalists and scientists had no right to publish a bit of code if it might be misused. In a similar case in April 2000, a U.S. court of appeals found that First Amendment protections did apply to software (Junger). Noting that source code has both an expressive feature and a functional feature, this court held that First Amendment protection is not reserved only for purely expressive communication. Yet in the DVD case, the court opposed this view and enforced the inflexible demands of the Digital Millennium Copyright Act. Notwithstanding Ted Nelson's characterisation of computers as literary machines, the decision meant that the linguistic and expressive aspects of software would be subordinated to other concerns. A simple series of symbols were thereby cast under a veil of legal secrecy. Although they were easy to discover, and capable of being committed to memory or translated to other languages, fair use and other intuitive freedoms were deemed expendable. These sorts of legal obstacles are serious challenges to the continued viability of free software like Linux. The central value proposition of Linux-based operating systems – free, open source code – is threatening to commercial competitors. Some corporations are intent on stifling further development of free alternatives. Patents offer another vulnerability. The writing of free software has become a minefield of potential patent lawsuits. Corporations have repeatedly chosen to pursue patent litigation years after the alleged infringements have been incorporated into widely used free software. For example, although it was designed to avoid patent problems by an array of international experts, the image file format known as JPEG (Joint Photographic Experts Group) has recently been dogged by patent infringement charges. Despite good intentions, low-budget initiatives and ad hoc organisations are ill equipped to fight profiteering patent lawsuits. One wonders whether software innovation is directed more by lawyers or computer scientists. The present copyright and patent regimes may serve the needs of the larger corporations, but it is doubtful that they are the best means of fostering software innovation and quality. Orwell wrote in his Homage to Catalonia, There was a new rule that censored portions of the newspaper must not be left blank but filled up with other matter; as a result it was often impossible to tell when something had been cut out. The development of the Internet has a similar character: new diversions spring up to replace what might have been so that the lost potential is hardly felt. The process of retrofitting Internet software to suit ideological and commercial agendas is already well underway. For example, Microsoft has announced recently that it will discontinue support for the Java language in 2004. The problem with Java, from Microsoft's perspective, is that it provides portable programming tools that work under all operating systems, not just Windows. With Java, programmers can develop software for the large number of Windows users, while simultaneously offering software to users of other operating systems. Java is an important piece of the software infrastructure for Internet content developers. Yet, in the interest of coercing people to use only their operating systems, Microsoft is willing to undermine thousands of existing Java-language projects. Their marketing hype calls this progress. The software industry relies on sales to survive, so if it means laying waste to good products and millions of hours of work in order to sell something new, well, that's business. The consequent infrastructure instability keeps software developers, and other creative people, on a treadmill. From Progressive Load by Andy Deck, artcontext.org/progload As an Internet content producer, one does not appeal directly to the hearts and minds of the public; one appeals through the medium of software and hardware. Since most people are understandably reluctant to modify the software running on their computers, the software installed initially is a critical determinant of what is possible. Unconventional, independent, and artistic uses of the Internet are diminished when the media infrastructure is effectively established by decree. Unaccountable corporate control over infrastructure software tilts the playing field against smaller content producers who have neither the advance warning of industrial machinations, nor the employees and resources necessary to keep up with a regime of strategic, cyclical obsolescence. It seems that independent content producers must conform to the distribution technologies and content formats favoured by the entertainment and marketing sectors, or else resign themselves to occupying the margins of media activity. It is no secret that highly diversified media corporations can leverage their assets to favour their own media offerings and confound their competitors. Yet when media giants AOL and Time-Warner announced their plans to merge in 2000, the claim of CEOs Steve Case and Gerald Levin that the merged companies would "operate in the public interest" was hardly challenged by American journalists. Time-Warner has since fought to end all ownership limits in the cable industry; and Case, who formerly championed third-party access to cable broadband markets, changed his tune abruptly after the merger. Now that Case has been ousted, it is unclear whether he still favours oligopoly. According to Levin, global media will be and is fast becoming the predominant business of the 21st century ... more important than government. It's more important than educational institutions and non-profits. We're going to need to have these corporations redefined as instruments of public service, and that may be a more efficient way to deal with society's problems than bureaucratic governments. Corporate dominance is going to be forced anyhow because when you have a system that is instantly available everywhere in the world immediately, then the old-fashioned regulatory system has to give way (Levin). It doesn't require a lot of insight to understand that this "redefinition," this slight of hand, does not protect the public from abuses of power: the dissolution of the "old-fashioned regulatory system" does not serve the public interest. From Lexicon by Andy Deck, artcontext.org/lexicon) As an artist who has adopted telecommunications networks and software as his medium, it disappoints me that a mercenary vision of electronic media's future seems to be the prevailing blueprint. The giantism of media corporations, and the ongoing deregulation of media consolidation (Ahrens), underscore the critical need for independent media sources. If it were just a matter of which cola to drink, it would not be of much concern, but media corporations control content. In this hyper-mediated age, content – whether produced by artists or journalists – crucially affects what people think about and how they understand the world. Content is not impervious to the software, protocols, and chicanery that surround its delivery. It is about time that people interested in independent voices stop believing that laissez faire capitalism is building a better media infrastructure. The German writer Hans Magnus Enzensberger reminds us that the media tyrannies that affect us are social products. The media industry relies on thousands of people to make the compromises necessary to maintain its course. The rapid development of the mind industry, its rise to a key position in modern society, has profoundly changed the role of the intellectual. He finds himself confronted with new threats and new opportunities. Whether he knows it or not, whether he likes it or not, he has become the accomplice of a huge industrial complex which depends for its survival on him, as he depends on it for his own. He must try, at any cost, to use it for his own purposes, which are incompatible with the purposes of the mind machine. What it upholds he must subvert. He may play it crooked or straight, he may win or lose the game; but he would do well to remember that there is more at stake than his own fortune (Enzensberger 18). Some cultural leaders have recognised the important role that free software already plays in the infrastructure of the Internet. Among intellectuals there is undoubtedly a genuine concern about the emerging contours of corporate, global media. But more effective solidarity is needed. Interest in open source has tended to remain superficial, leading to trendy, cosmetic, and symbolic uses of terms like "open source" rather than to a deeper commitment to an open, public information infrastructure. Too much attention is focussed on what's "cool" and not enough on the road ahead. Various media specialists – designers, programmers, artists, and technical directors – make important decisions that affect the continuing development of electronic media. Many developers have failed to recognise (or care) that their decisions regarding media formats can have long reaching consequences. Web sites that use media formats which are unworkable for open source operating systems should be actively discouraged. Comparable technologies are usually available to solve compatibility problems. Going with the market flow is not really giving people what they want: it often opposes the work of thousands of activists who are trying to develop open source alternatives (see e.g. Greene). Average Internet users can contribute to a more innovative, free, open, and independent media – and being conscientious is not always difficult or unpleasant. One project worthy of support is the Internet browser Mozilla. Currently, many content developers create their Websites so that they will look good only in Microsoft's Internet Explorer. While somewhat understandable given the market dominance of Internet Explorer, this disregard for interoperability undercuts attempts to popularise standards-compliant alternatives. Mozilla, written by a loose-knit group of activists and programmers (some of whom are paid by AOL/Time-Warner), can be used as an alternative to Microsoft's browser. If more people use Mozilla, it will be harder for content providers to ignore the way their Web pages appear in standards-compliant browsers. The Mozilla browser, which is an open source initiative, can be downloaded from http://www.mozilla.org/. While there are many people working to create real and lasting alternatives to the monopolistic and technocratic dynamics that are emerging, it takes a great deal of cooperation to resist the media titans, the FCC, and the courts. Oddly enough, corporate interests sometimes overlap with those of the public. Some industrial players, such as IBM, now support open source software. For them it is mostly a business decision. Frustrated by the coercive control of Microsoft, they support efforts to develop another operating system platform. For others, including this writer, the open source movement is interesting for the potential it holds to foster a more heterogeneous and less authoritarian communications infrastructure. Many people can find common cause in this resistance to globalised uniformity and consolidated media ownership. The biggest challenge may be to get people to believe that their choices really matter, that by endorsing certain products and operating systems and not others, they can actually make a difference. But it's unlikely that this idea will flourish if artists and intellectuals don't view their own actions as consequential. There is a troubling tendency for people to see themselves as powerless in the face of the market. This paralysing habit of mind must be abandoned before the media will be free. Works Cited Ahrens, Frank. "Policy Watch." Washington Post (23 June 2002): H03. 30 March 2003 <http://www.washingtonpost.com/ac2/wp-dyn/A27015-2002Jun22?la... ...nguage=printer>. Batt, William. "How Our Towns Got That Way." 7 Oct. 1996. 31 March 2003 <http://www.esb.utexas.edu/drnrm/WhatIs/LandValue.htm>. Chester, Jeff. "Gerald Levin's Negative Legacy." Alternet.org 6 Dec. 2001. 5 March 2003 <http://www.democraticmedia.org/resources/editorials/levin.php>. Enzensberger, Hans Magnus. "The Industrialisation of the Mind." Raids and Reconstructions. London: Pluto Press, 1975. 18. Greene, Thomas C. "MS to Eradicate GPL, Hence Linux." 25 June 2002. 5 March 2003 <http://www.theregus.com/content/4/25378.php>. Hopper, D. Ian. "FBI Pushes for Cyber Ethics Education." Associated Press 10 Oct. 2000. 29 March 2003 <http://www.billingsgazette.com/computing/20001010_cethics.php>. Junger v. Daley. U.S. Court of Appeals for 6th Circuit. 00a0117p.06. 2000. 31 March 2003 <http://pacer.ca6.uscourts.gov/cgi-bin/getopn.pl?OPINION=00a0... ...117p.06>. Levin, Gerald. "Millennium 2000 Special." CNN 2 Jan. 2000. Touretzky, D. S. "Gallery of CSS Descramblers." 2000. 29 March 2003 <http://www.cs.cmu.edu/~dst/DeCSS/Gallery>. Links http://artcontext.org/lexicon/ http://artcontext.org/progload http://pacer.ca6.uscourts.gov/cgi-bin/getopn.pl?OPINION=00a0117p.06 http://www.billingsgazette.com/computing/20001010_cethics.html http://www.cs.cmu.edu/~dst/DeCSS/Gallery http://www.democraticmedia.org/resources/editorials/levin.html http://www.esb.utexas.edu/drnrm/WhatIs/LandValue.htm http://www.mozilla.org/ http://www.theregus.com/content/4/25378.html http://www.washingtonpost.com/ac2/wp-dyn/A27015-2002Jun22?language=printer Citation reference for this article Substitute your date of access for Dn Month Year etc... MLA Style Deck, Andy. "Treadmill Culture " M/C: A Journal of Media and Culture< http://www.media-culture.org.au/0304/04-treadmillculture.php>. APA Style Deck, A. (2003, Apr 23). Treadmill Culture . M/C: A Journal of Media and Culture, 6,< http://www.media-culture.org.au/0304/04-treadmillculture.php>

Introduction Many people interpret the word ‘cult’ through specific connotations, including, but not limited to, a community of like-minded people on the edge of civilization, often led by a charismatic leader, with beliefs that are ‘other’ to societal ‘norms’. Cults are often perceived as deviant, regularly incorporating elements of crime, especially physical and sexual violence. The adoption by some cults of a special uniform or dress code has been readily picked up by popular culture and has become a key ‘defining’ characteristic of the nature of a cult. In this article, we use the semiotic framework of myth, as discussed by Barthes, to demonstrate how cult uniforms become semiotic myths of popular culture. Narratively, the myth of the cult communicates violence, deviance, manipulation, and brainwashing. The myth of on-screen cults has derived itself from a reflexive pop culture foundation. From popular culture inspiring cults to cults inspiring popular culture and back again, society generates its cult myth through three key mechanisms: medicalisation, deviance amplification, and convergence. This means we are at risk of misrepresenting the true nature of cults, creating a definition incongruent with reality. This article traces the history of cults, the expectations of cult behaviour, and the semiotics of uniforms to start the discussion on why society is primed to accept a confusion between nature and the semiotic messaging of “what-goes-without-saying” (Barthes Mythologies 11). Semiotics and Myth Following the basic groundwork of de Saussure in the early 1900s, semiotics is the study of signs and how we use signs to derive meaning from the external world (de Saussure). Barthes expanded on this with his series of essays in Mythologies, adding a layer of connotation that leads to myth (Barthes Mythologies). Connotation, as described by Barthes, is the interaction between signs, feelings, and values. The connotations assigned to objects and concepts become a system of communication that is a message, the message becomes myth. The myth is not defined by the object or concept, but by the way society collectively understands it and all its connotations (Barthes Elements of Semiology 89-91). For scholars like Barthes, languages and cultural artifacts lend themselves to myth because many of our concepts are vague and abstract. Because the concept is vague, it is easy to impose our own values and ideologies upon it. This also means different people can interpret the same concept in different ways (Barthes Mythologies 132). The concept of a cult is no exception. Cults mean different things to different people and the boundaries between cults and religious or commercial organisations are often contested. As a pop culture artifact, the meaning of cults has been generated through repeated exposure in different media and genres. Similarly, pop culture (tv, films, news, etc.) often has the benefit of fiction, which separates itself from the true nature of cults (sensu Barthes Mythologies). Yet, through repeated exposure, we begin to share a universal meaning for the term and all the behaviours understood within the myth. Our repeated exposure to the signs of cults in pop culture is the combined effect of news media and fiction slowly building upon itself in a reflexive manner. We hear news reports of cults behaving in obscure ways, followed by a drama, parody, critique, or satire in a fictitious story. The audience then begins to see the repeated narrative as evidence to the true nature of cults. Over time the myth of the cult naturalises into the zeitgeist as concretely as any other sign, word, or symbol. Once the myth is naturalised, it is better used as a narrative device when affixed to a universally recognised symbol, such as the uniform. The uniform becomes an efficient device for communicating meaning in a short space of time. We argue that the concept of cult as myth has entered a collective understanding, and so, it is necessary to reflect on the mechanisms that drove the correlations which ultimately created the myth. Barthes’s purpose for analysing myth was “to track down, in the decorative display of what-goes-without-saying, the ideological abuse which, in my view, is hidden there” (Barthes Mythologies 11). For this reason, we must briefly look at the history of cults and their relationship with crime. A Brief History of Cults ‘Cult’ derives from the Latin root, cultus, or cultivation, and initially referred to forms of religious worship involving special rituals and ceremonies directed towards specific figures, objects, and/or divine beings. Early to mid-twentieth century sociologists adopted and adapted the term to classify a kind of religious organisation and later to signal new forms of religious expression not previously of primary or singular interest to the scholar of religion (Campbell; Jackson and Jobling; Nelson). The consequences were such that ‘cult’ came to carry new weight in terms of its meaning and reception, and much like other analytical concepts developed an intellectual significance regarding religious innovation it had not previously possessed. Unfortunately, this was not to last. By the early 1990s, ‘cult’ had become a term eschewed by scholars as pejorative, value-laden, and disparaging of its supposed subject matter; a term denuded of technical and descriptive meaning and replaced by more value-neutral alternatives (Dillon and Richardson; Richardson; Chryssides and Zeller). Results from well-published surveys (Pfeifer; Olson) and our own experience in teaching related subject matter revealed predominantly negative attitudes towards the term ‘cult’, with the inverse true for the alternative descriptors. Perhaps more importantly, the surveys revealed that for the public majority, knowledge of ‘cults’ came via media reportage of particularly the sensational few, rather than from direct experience of new religions or their members more generally (Pfeifer). For example, the Peoples Temple, Branch Davidian, and Heaven’s Gate groups featured heavily in news and mass media. Importantly, reporting of each of the tragic events marking their demise (in 1978, 1993, and 1997 respectively) reinforced a burgeoning stereotype and escalated fears about cults in our midst. The events in Jonestown, Guyana (Peoples Temple), especially, bolstered an anticult movement of purported cult experts and deprogrammers offering to save errant family members from the same fate as those who died [there]. The anticult movement portrayed all alleged cults as inherently dangerous and subject only to internal influences. They figured the charismatic leader as so powerful that he could take captive the minds of his followers and make them do whatever he wanted. (Crockford 95) While the term ‘new religious movement’ (NRM) has been used in place of cults within the academic sphere, ‘cult’ is still used within popular culture contexts precisely because of the connotations it inspires, with features including charismatic leaders, deprogrammers, coercion and mind-control, deception, perversion, exploitation, deviance, religious zealotry, abuse, violence, and death. For this reason, we still use the word cult to mean the myth of the cult as represented by popular culture. Representations of Cults and Expectations of Crime Violence and crime can be common features of some cults. Most NRMs “stay within the boundaries of the law” and practice their religion peacefully (Szubin, Jensen III, and Gregg 17). Unfortunately, it is usually those cults that are engaged in violence and crime that become newsworthy, and thus shape public ‘knowledge’ about the nature of cults and drive public expectations. Two of America’s most publicised cults, Charles Manson and the Manson Family and the Peoples Temple, are synonymous with violence and crime. Prior to committing mass suicide by poison in Jonestown, the Peoples Temple accumulated many guns as well as killing Congressman Leo Ryan and members of his party. Similarly, Charles Manson and the Manson Family stockpiled weapons, participated in illegal drug use, and murdered seven people, including Hollywood actor Sharon Tate. The high-profile victims of both groups ensured ongoing widespread media attention and continuous popular culture interest in both groups. Other cults are more specifically criminal in nature: for example, the Constanzo group in Matamoros, while presenting as a cult, are also a drug gang, leading to many calling these groups narco-cults (Kail 56). Sexual assault and abuse are commonly associated with cults. There have been numerous media reports worldwide on the sexual abuse of (usually) women and/or children. For example, a fourteen-year-old in the Children of God group alleged that she was raped when she disobeyed a leader (Rudin 28). In 2021, the regional city of Armidale, Australia, became national news when a former soldier was arrested on charges of “manipulating a woman for a ‘cult’ like purpose” (McKinnell). The man, James Davis, styles himself as the patriarch of a group known as the ‘House of Cadifor’. Police evidence includes six signed “slavery contracts”, as well as 70 witnesses to support the allegation that Mr Davis subjected a woman to “ongoing physical, sexual and psychological abuse and degradation” as well as unpaid prostitution and enslavement (McKinnell). Cults and Popular Culture The depiction of cults in popular culture is attracting growing attention. Scholars Lynn Neal (2011) and Joseph Laycock (2013) have initiated this research and identified consistent stereotypes of 'cults’ being portrayed throughout popular media. Neal found that cults began to be featured in television shows as early as the 1950s and 1960s, continually escalating until the 1990s before dropping slightly between 2000 and 2008 (the time the research was concluded). Specifically, there were 10 episodes between 1958-1969; 19 in the 1970s, which Neal attributes to the “rise of the cult scare and intense media scrutiny of NRMs” (97); 25 in the 1980s; 72 in the 1990s; and 59 between 2000 and 2008. Such academic research has identified that popular culture is important in the formation of the public perception, and social definition, of acceptable and deviant religions (Laycock 81). Laycock argues that representations of cults in popular culture reinforces public narratives about cults in three important ways: medicalisation, deviance amplification, and convergence. Medicalisation refers to the depiction of individuals becoming brainwashed and deprogrammed. The medicalisation of cults can be exacerbated by the cult uniform and clinical, ritualistic behaviours. Deviance amplification, a term coined by Leslie Wilkins in the 1960s, is the phenomenon of ‘media hype’, where the media selects specific examples of deviant behaviour, distorting them (Wilkins), such that a handful of peripheral cases appears representative of a larger social problem (Laycock 84). Following the deviance amplification, there is then often a 'moral panic' (a term coined by Stanley Cohen in 1972) where the problem is distorted and heightened within the media. Cults are often subject to deviance amplification within the media, leading to moral panics about the ‘depraved’, sexual, criminal, and violent activities of cults preying on and brainwashing innocents. Convergence “is a rhetorical device associated with deviance amplification in which two or more activities are linked so as to implicitly draw a parallel between them” (Laycock 85). An example of convergence occurred when the Branch Davidians were compared to the Peoples Temple, ultimately leading the FBI “to end the siege through an aggressive ‘dynamic entry’ in part because they feared such a mass suicide” (Laycock 85). The FBI transferred responsibility for the deaths to ‘mass suicide’, which has become the common narrative of events at Waco. Each of the three mechanisms have an important role to play in the popular culture presentation of cults to audiences. Popular media sources, fictional or not, are incentivised to present the most diabolical cult to the audience – and this often includes the medicalised elements of brainwashing and manipulation. This presentation reinforces existing deviance amplification and moral panics around the depraved activities of cults, and in particular sexual and criminal activities. And finally, convergence acts as a 'cultural script’ where the portrayal of these types of characteristics (brainwashing, criminal or violent behaviour, etc.) is automatically associated with cults. As Laycock argues, “in this way, popular culture has a unique ability to promote convergence and, by extension, deviance amplification” (85). The mechanisms of medicalisation, deviance amplification and convergence are important to the semiotic linking of concepts, signs, and signifiers in the process of myth generation. In efficiently understanding the message of the myth, the viewer must have a sign they can affix to it. In the case of visual mediums this must be immediate and certain. As many of the convergent properties of cults are behavioural (acts of violence and depravity, charismatic leaders, etc.), we need a symbol that audiences can understand immediately. Uniforms achieve this with remarkable efficiency. Upon seeing a still, two-dimensional image of people wearing matching garb it can be made easily apparent that they are part of a cult. Religious uniforms are one of the first visual images one conjures upon hearing the word cult: “for most people the word ‘cult’ conjures up ‘60s images of college students wearing flowing robes, chanting rhythmically and spouting Eastern philosophy” (Salvatore cited in Petherick 577; italics in original). The impact is especially pronounced if the clothes are atypical, anachronistic, or otherwise different to the expected clothes of the context. This interpretation then becomes cemented through the actions of the characters. In Rick and Morty, season 1, episode 10, Morty is imprisoned with interdimensional versions of himself. Despite some morphological differences, each Morty is wearing his recognisable yellow top and blue pants. While our Morty’s back is turned, five hooded, robed figures in atypical garb with matching facial markings approach Morty. The audience is immediately aware that this is a cult. The comparison between the uniform of Morty and the Morty cult exemplifies the use of cult uniform in the myth of Cults. The cult is then cemented through chanting and a belief in the “One true Morty” (Harmon et al.). Semiotics, Clothes, and Uniforms The semiotics of clothes includes implicit, explicit, and subliminal signs. The reasons we choose to wear what we wear is governed by multiple factors both within our control and outside of it: for instance, our body shape, social networks and economic status, access to fashion and choice (Barthes The Fashion System; Hackett). We often choose to communicate aspects of our identity through what we wear or what we choose not to wear. Our choice of clothing communicates aspects of who we are, but also who we want to be (Hackett; Simmel; Veblen) Uniforms are an effective and efficient communicative device. Calefato’s classification of uniforms is not only as those used by military and working groups, but also including the strictly coded dress of subcultures. Unlike other clothes which can be weakly coded, uniforms differentiate themselves through their purposeful coded signalling system (Calefato). To scholars such as Jennifer Craik, uniforms intrigue us because they combine evident statements as well as implied and subliminal communications (Craik). Theories about identity predict that processes similar to the defining of an individual are also important to group life, whereby an individual group member's conceptualisation of their group is derived from the collective identity (Horowitz; Lauger). Collective identities are regularly emphasised as a key component in understanding how groups gain meaning and purpose (Polletta and Jasper). The identity is generally constructed and reinforced through routine socialisation and collective action. Uniforms are a well-known means of creating collective identities. They restrict one’s clothing choices and use boundary-setting rituals to ensure commitment to the group. In general, the more obvious the restriction, the easier it is to enforce. Demanding obvious behaviours from members, unique to the community, simultaneously generates a differentiation between the members and non-members, while enabling self-enforcement and peer-to-peer judgments of commitment. Leaders of religious movements like cults and NRMs will sometimes step back from the punitive aspects of nonconformity. Instead, it falls to the members to maintain the discipline of the collective (Kelley 109). This further leads to a sense of ownership and therefore belonging to the community. Uniforms are an easy outward-facing signal that allows for ready discrimination of error. Because they are often obvious and distinctive dress, they constrain and often stigmatise members. In other collective situations such as with American gangs, even dedicated members will deny their gang affiliation if it is advantageous to do so (Lauger Real Gangstas). While in uniform, individuals cannot hide their membership, making the sacrifice more costly. Members are forced to take one hundred percent of the ownership and participate wholly, or not at all. Through this mechanism, cults demonstrate the medicalisation of the members. Leaders may want their members to be unable to escape or deny affiliation. Similarly, their external appearances might invite persecution and therefore breed resilience, courage, and solidarity. It is, in essence, a form of manipulation (see for instance Iannaccone). Alternatively, as Melton argues, members may want to be open and proud of their organisation, as displayed through them adopting their uniforms (15). The uniform of cults in popular media is a principal component of medicalisation, deviance amplification, and convergence. The uniform, often robes, offers credence to the medicalisation aspect: members of cults are receiving ‘treatment’ — initially, negative treatment while being brainwashed, and then later helpful/saving treatment when being deprogrammed, providing they survive a mass suicide attempt and/or, criminal, sexual, or violent escapades. Through portraying cult members in a distinctive uniform, there is no doubt for the audience who is receiving or in need of treatment. Many of the cults portrayed on screen can easily communicate the joining of a cult by changing the characters' dress. Similarly, by simply re-dressing the character, it is communicated that the character has returned to normal, they have been saved, they are a survivor. In Unbreakable Kimmy Schmidt, while three of the four ‘Mole women’ integrate back into society, Gretchen Chalker continues to believe in their cult; as such she never takes of her cult uniform. In addition, the employment of uniforms for cult members in popular culture enables an instant visual recognition of ‘us’ and ‘them’, or ‘normal’ and ‘abnormal’, and reinforces stereotypical notions of social order and marginalised, deviant (religious) groups (Neal 83). The clothing differences are obvious in The Simpsons season 9, episode 13, “Joy of Sect”: ‘Movementarian’ members, including the Simpsons, don long flowing robes. The use of cult uniform visualises their fanatical commitment to the group. It sets them apart from the rest of Springfield and society (Neal 88-89). The connection between uniforms and cults derives two seemingly paradoxical meanings. Firstly, it reduces the chances of the audience believing that the cult employed ‘deceptive recruiting’ techniques. As Melton argues, because of the association our society has with uniforms and cults, “it is very hard for someone to join most new religions, given their peculiar dress and worship practices, without knowing immediately its religious nature” (14). As such, within popular media, the presence of the uniform increases the culpability of those who join the cult. Contrarily, the character in uniform is a sign that the person has been manipulated and/or brainwashed. This reduces the culpability of the cult member. However, the two understandings are not necessarily exclusive. It is possible to view the cult member as a naïve victim, someone who approached the cult as an escape from their life but was subsequently manipulated into behaving criminally. This interpretation is particularly powerful because it indicates cults can prey on anyone, and that anyone could become a victim of a cult. This, in turn, heightens the moral panic surrounding cults and NRMs. The on-screen myth of the cult as represented by its uniform has a basis in the real-life history of NRMs. Heaven’s Gate members famously died after they imbibed fatal doses of alcohol and barbiturates to achieve their ‘final exit’. Most members were found laid out on beds covered in purple shrouds, all wearing matching black shirts, black pants, and black and white Nike shoes. The famous photos of Warren Jeffs’s polygamous Fundamentalist Church of Jesus Christ of Latter-Day Saints, the subject of Netflix’s Keep Sweet: Pray and Obey, depict multiple women in matching conservative dresses with matching hairstyles gathered around a photo of Jeffs. The image and uniform are a clear influence on the design of Unbreakable’s ‘Mole women’. A prime example of the stereotype of cult uniforms is provided by the Canadian comedy program The Red Green Show when the character Red tells Harold “cults are full of followers, they have no independent thought, they go to these pointless meetings ... they all dress the same” (episode 165). The statement is made while the two main characters Red and Harold are standing in matching outfits. Blurring Nature and Myth Importantly, the success of these shows very much relies on audiences having a shared conception of NRMs and the myth of the cult. This is a curious combination of real and fictional knowledge of the well-publicised controversial events in history. Fictional cults frequently take widely held perspectives of actual religious movements and render them either more absurd or more frightening (Laycock 81). Moreover, the blurring of fictional and non-fictional groups serves to reinforce the sense that all popular culture cults and their real-world counterparts are the same; that they all follow a common script. In this, there is convergence between the fictional and the real. The myth of the cult bleeds from the screen into real life. The Simpsons’ “The Joy of Sect” was televised in the year following the suicide of the 39 members of the Heaven’s Gate group, and the storyline in part was influenced by it. Importantly, as a piercing, satirical critique of middle-class America, the “Joy of Sect” not only parodied traditional and non-traditional religion generally (as well as the ‘cult-like’ following of mass media such as Fox); scholars have shown that it also parodied the ‘cult’ stereotype itself (Feltmate). While Heaven’s Gate influenced to a greater or lesser extent each of the TV shows highlighted thus far, it was also the case that the group incorporated into its eschatology aspects of popular culture linked primarily to science fiction. For example, group members were known to have regularly watched and discussed episodes of Star Trek (Hoffmann and Burke; Sconce), adopting aspects of the show’s vernacular in “attempts to relate to the public” (Gate 163). Words such as ‘away-team’, ‘prime-directive’, ‘hologram’, ‘Captain’, ‘Admiral’, and importantly ‘Red-Alert’ were adopted; the latter, often signalling code-red situations in Star Trek episodes, appeared on the Heaven’s Gate Website in the days just prior to their demise. Importantly, allusions to science fiction and Star Trek were incorporated into the group’s self-styled ‘uniform’ worn during their tragic ritual-suicide. Stitched into the shoulders of each of their uniforms were triangular, Star Trek-inspired patches featuring various celestial bodies along with a tagline signalling the common bond uniting each member: “Heaven’s Gate Away Team” (Sconce). Ironically, with replica patches readily for sale online, and T-shirts and hoodies featuring modified though similar Heaven’s Gate symbolism, this ‘common bond’ has been commodified in such a way as to subvert its original meaning – at least as it concerned ‘cult’ membership in the religious context. The re-integration of cult symbols into popular culture typifies the way we as a society detachedly view the behaviours of cults. The behaviour of cults is anecdotally viewed through a voyeuristic lens, potentially exacerbated by the regular portrayals of cults through parody. Scholars have demonstrated how popular culture has internationally impacted on criminological aspects of society. For instance, there was a noted, international increase in unrealistic expectations of jurors wanting forensic evidence during court cases after the popularity of forensic science in crime dramas (Franzen; Wise). After the arrest of James Davis in Armidale, NSW, Australia, the Sydney Morning Herald reported that Davis was the patriarch of the “House of Cadifor” and he was part of a “cult” (both reported in inverted commas). The article also includes an assumption from Davis's lawyer that, in discussing the women of the group, “the Crown might say ‘they’ve been brainwashed’”. Similarly, the article references the use of matching collars by the women (Mitchell). Nine News reported that the “ex-soldier allegedly forced tattooed, collared sex slave into prostitution”, bringing attention to the clothing as part of the coercive techniques of Davis. While the article does not designate the House of Cadifor as a cult, they include a quote from the Assistant Commissioner Justine Gough, “Mr Davis' group has cult-like qualities”, and included the keyword ‘cults’ for the article. Regrettably, the myth of cults and real-world behaviours of NRMs do not always align, and a false convergence is drawn between the two. Furthermore, the consistent parodying and voyeuristic nature of on-screen cults means we might be at fault of euphemising the crimes and behaviours of those deemed to be part of a ‘cult’. Anecdotally, the way Armidale locals discussed Davis was through a lens of excitement and titillation, as if watching a fictional story unfold in their own backyard. The conversations and news reporting focussed on the cult-like aspects of Davis and not the abhorrence of the alleged crimes. We must remain mindful that the cinematic semiology of cults and the myth as represented by their uniform dress and behaviours is incongruent with the nature of NRMs. However, more work needs to be done to better understand the impact of on-screen cults on real-world attitudes and beliefs. Conclusion The myth of the cult has entered a shared understanding within today’s zeitgeist, and the uniform of the cult stands at its heart as a key sign of the myth. Popular culture plays a key role in shaping this shared understanding by following the cultural script, slowly layering fact with fiction, just as fact begins to incorporate the fiction. The language of the cult as communicated through their uniforms is, we would argue, universally understood and purposeful. The ubiquitous representation of cults portrays a deviant group, often medicalised, and subject to deviance amplification and convergence. When a group of characters is presented to the audience in the same cult dress, we know what is being communicated to us. Fictional cults in popular culture continue to mirror the common list of negative features attributed to many new religious movements. Such fictional framing has come to inform media-consumer attitudes in much the same way as news media, reflecting as they do the cultural stock of knowledge from which our understandings are drawn, and which has little grounding in the direct or immediate experience of the phenomena in question. In short, the nature of NRMs has become confused with the myth of the cult. More research is needed to understand the impact of the myth of the cult. However, it is important to ensure “what-goes-without-saying” is not obfuscating, euphemising, or otherwise misrepresenting nature. References Barthes, Roland. Elements of Semiology. London: Jonathon Cape, 1967. ———. The Fashion System. U of California P, 1990. ———. Mythologies. Trans. 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'He did what the cipher could not, he rescued himself.' -- Alfred Bester, The Stars My Destination (23) On many levels, the new Nine Inch Nails album The Fragile is a gritty meditation about different types of End: the eternal relationship cycle of 'fragility, tension, ordeal, fragmentation' (adapted, with apologies to Wilhelm Reich); fin-de-siècle anxiety; post-millennium foreboding; a spectre of the alien discontinuity that heralds an on-rushing future vastly different from the one envisaged by Enlightenment Project architects. In retrospect, it's easy for this perspective to be dismissed as jargon-filled cyber-crit hyperbole. Cyber-crit has always been at its best too when it invents pre-histories and finds hidden connections between different phenomena (like the work of Greil Marcus and early Mark Dery), and not when it is closer to Chinese Water Torture, name-checking the canon's icons (the 'Deleuze/Guattari' tag-team), texts and key terms. "The organization of sound is interpreted historically, politically, socially ... . It subdues music's ambition, reins it in, restores it to its proper place, reconciles it to its naturally belated fate", comments imagineer Kodwo Eshun (4) on how cyber-crit destroys albums and the innocence of the listening experience. This is how official histories are constructed a priori and freeze-dried according to personal tastes and prior memes: sometimes the most interesting experiments are Darwinian dead-ends that fail to make the canon, or don't register on the radar. Anyone approaching The Fragile must also contend with the music industry's harsh realities. For every 10 000 Goth fans who moshed to the primal 'kill-fuck-dance' rhythms of the hit single "Closer" (heeding its siren-call to fulfil basic physiological needs and build niche-space), maybe 20 noted that the same riff returned with a darker edge in the title track to The Downward Spiral, undermining the glorification of Indulgent hedonism. "The problem with such alternative audiences," notes Disinformation Creative Director Richard Metzger, "is that they are trying to be different -- just like everyone else." According to author Don Webb, "some mature Chaos and Black Magicians reject their earlier Nine Inch Nails-inspired Goth beginnings and are extremely critical towards new adopters because they are uncomfortable with the subculture's growing popularity, which threatens to taint their meticulously constructed 'mysterious' worlds. But by doing so, they are also rejecting their symbolic imprinting and some powerful Keys to unlocking their personal history." It is also difficult to separate Nine Inch Nails from the commercialisation and colossal money-making machine that inevitably ensued on the MTV tour circuit: do we blame Michael Trent Reznor because most of his audience are unlikely to be familiar with 'first-wave' industrial bands including Cabaret Voltaire and the experiments of Genesis P. Orridge in Throbbing Gristle? Do we accuse Reznor of being a plagiarist just because he wears some of his influences -- Dr. Dre, Daft Punk, Atari Teenage Riot, Pink Floyd's The Wall (1979), Tom Waits's Bone Machine (1992), David Bowie's Low (1977) -- on his sleeve? And do we accept no-brain rock critic album reviews who quote lines like 'All the pieces didn't fit/Though I really didn't give a shit' ("Where Is Everybody?") or 'And when I suck you off/Not a drop will go to waste' ("Starfuckers Inc") as representative of his true personality? Reznor evidently has his own thoughts on this subject, but we should let the music speak for itself. The album's epic production and technical complexity turned into a post-modern studio Vision Quest, assisted by producer Alan Moulder, eleventh-hour saviour Bob Ezrin (brought in by Reznor to 'block-out' conceptual and sonic continuity), and a group of assault-technicians. The fruit of these collaborations is an album where Reznor is playing with our organism's time-binding sense, modulating strange emotions through deeply embedded tonal angularities. During his five-year absence, Trent Reznor fought diverse forms of repetitious trauma, from endogenous depression caused by endless touring to the death of his beloved grandmother (who raised him throughout childhood). An end signals a new beginning, a spiral is an open-ended and ever-shifting structure, and so Reznor sought to re-discover the Elder Gods within, a shamanic approach to renewal and secular salvation utilised most effectively by music PR luminary and scientist Howard Bloom. Concerned with healing the human animal through Ordeals that hard-wire the physiological baselines of Love, Hate and Fear, Reznor also focusses on what happens when 'meaning-making' collapses and hope for the future cannot easily be found. He accurately captures the confusion that such dissolution of meaning and decline of social institutions brings to the world -- Francis Fukuyama calls this bifurcation 'The Great Disruption'. For a generation who experienced their late childhood and early adolescence in Reagan's America, Reznor and his influences (Marilyn Manson and Filter) capture the Dark Side of recent history, unleashed at Altamont and mutating into the Apocalyptic style of American politics (evident in the 'Star Wars'/SDI fascination). The personal 'psychotic core' that was crystallised by the collapse of the nuclear family unit and supportive social institutions has returned to haunt us with dystopian fantasies that are played out across Internet streaming media and visceral MTV film-clips. That such cathartic releases are useful -- and even necessary (to those whose lives have been formed by socio-economic 'life conditions') is a point that escapes critics like Roger Scruton, some Christian Evangelists and the New Right. The 'escapist' quality of early 1980s 'Rapture' and 'Cosmocide' (Hal Lindsey) prophecies has yielded strange fruit for the Children of Ezekiel, whom Reznor and Marilyn Manson are unofficial spokes-persons for. From a macro perspective, Reznor's post-human evolutionary nexus lies, like J.G. Ballard's tales, in a mythical near-future built upon past memory-shards. It is the kind of worldview that fuses organic and morphogenetic structures with industrial machines run amok, thus The Fragile is an artefact that captures the subjective contents of the different mind produced by different times. Sonic events are in-synch but out of phase. Samples subtly trigger and then scramble kinaesthetic-visceral and kinaesthetic-tactile memories, suggestive of dissociated affective states or body memories that are incapable of being retrieved (van der Kolk 294). Perhaps this is why after a Century of Identity Confusion some fans find it impossible to listen to a 102-minute album in one sitting. No wonder then that the double album is divided into 'left' and 'right' discs (a reference to split-brain research?). The real-time track-by-track interpretation below is necessarily subjective, and is intended to serve as a provisional listener's guide to the aural ur-text of 1999. The Fragile is full of encrypted tones and garbled frequencies that capture a world where the future is always bleeding into a non-recoverable past. Turbulent wave-forms fight for the listener's attention with prolonged static lulls. This does not make for comfortable or even 'nice' listening. The music's mind is a snapshot, a critical indicator, of the deep structures brewing within the Weltanschauung that could erupt at any moment. "Somewhat Damaged" opens the album's 'Left' disc with an oscillating acoustic strum that anchor's the listener's attention. Offset by pulsing beats and mallet percussion, Reznor builds up sound layers that contrast with lyrical epitaphs like 'Everything that swore it wouldn't change is different now'. Icarus iconography is invoked, but perhaps a more fitting mythopoeic symbol of the journey that lies ahead would be Nietzsche's pursuit of his Ariadne through the labyrinth of life, during which the hero is steadily consumed by his numbing psychosis. Reznor fittingly comments: 'Didn't quite/Fell Apart/Where were you?' If we consider that Reznor has been repeating the same cycle with different variations throughout all of his music to date, retro-fitting each new album into a seamless tapestry, then this track signals that he has begun to finally climb out of self-imposed exile in the Underworld. "The Day the World Went Away" has a tremendously eerie opening, with plucked mandolin effects entering at 0:40. The main slashing guitar riff was interpreted by some critics as Reznor's attempt to parody himself. For some reason, the eerie backdrop and fragmented acoustic guitar strums recalls to my mind civil defence nuclear war films. Reznor, like William S. Burroughs, has some powerful obsessions. The track builds up in intensity, with a 'Chorus of the Damned' singing 'na na nah' over apocalyptic end-times imagery. At 4:22 the track ends with an echo that loops and repeats. "The Frail" signals a shift to mournful introspectiveness with piano: a soundtrack to faded 8 mm films and dying memories. The piano builds up slowly with background echo, holds and segues into ... "The Wretched", beginning with a savage downbeat that recalls earlier material from Pretty Hate Machine. 'The Far Aways/Forget It' intones Reznor -- it's becoming clear that despite some claims to the contrary, there is redemption in this album, but it is one borne out of a relentless move forward, a strive-drive. 'You're finally free/You could be' suggest Reznor studied Existentialism during his psychotherapy visits. This song contains perhaps the ultimate post-relationship line: 'It didn't turn out the way you wanted it to, did it?' It's over, just not the way you wanted; you can always leave the partner you're with, but the ones you have already left will always stain your memories. The lines 'Back at the beginning/Sinking/Spinning' recall the claustrophobic trapped world and 'eternal Now' dislocation of Post-Traumatic Stress Disorder victims. At 3:44 a plucked cello riff, filtered, segues into a sludge buzz-saw guitar solo. At 5:18 the cello riff loops and repeats. "We're in This Together Now" uses static as percussion, highlighting the influence of electricity flows instead of traditional rock instrument configurations. At 0:34 vocals enter, at 1:15 Reznor wails 'I'm impossible', showing he is the heir to Roger Waters's self-reflective rock-star angst. 'Until the very end of me, until the very end of you' reverts the traditional marriage vow, whilst 'You're the Queen and I'm the King' quotes David Bowie's "Heroes". Unlike earlier tracks like "Reptile", this track is far more positive about relationships, which have previously resembled toxic-dyads. Reznor signals a delta surge (breaking through barriers at any cost), despite a time-line morphing between present-past-future. At 5:30 synths and piano signal a shift, at 5:49 the outgoing piano riff begins. The film-clip is filled with redemptive water imagery. The soundtrack gradually gets more murky and at 7:05 a subterranean note signals closure. "The Fragile" is even more hopeful and life-affirming (some may even interpret it as devotional), but this love -- representative of the End-Times, alludes to the 'Glamour of Evil' (Nico) in the line 'Fragile/She doesn't see her beauty'. The fusion of synths and atonal guitars beginning at 2:13 summons forth film-clip imagery -- mazes, pageants, bald eagles, found sounds, cloaked figures, ruined statues, enveloping darkness. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Just like You Imagined" opens with Soundscapes worthy of Robert Fripp, doubled by piano and guitar at 0:39. Drums and muffled voices enter at 0:54 -- are we seeing a pattern to Reznor's writing here? Sonic debris guitar enters at 1:08, bringing forth intensities from white noise. This track is full of subtle joys like the 1:23-1:36 solo by David Bowie pianist Mike Garson and guitarist Adrian Belew's outgoing guitar solo at 2:43, shifting back to the underlying soundscapes at 3:07. The sounds are always on the dissipative edge of chaos. "Pilgrimage" utilises a persistent ostinato and beat, with a driving guitar overlay at 0:18. This is perhaps the most familiar track, using Reznor motifs like the doubling of the riff with acoustic guitars between 1:12-1:20, march cries, and pitch-shift effects on a 3:18 drumbeat/cymbal. Or at least I could claim it was familiar, if it were not that legendary hip-hop producer and 'edge-of-panic' tactilist Dr. Dre helped assemble the final track mix. "No, You Don't" has been interpreted as an attack on Marilyn Manson and Hole's Courntey Love, particularly the 0:47 line 'Got to keep it all on the outside/Because everything is dead on the inside' and the 2:33 final verse 'Just so you know, I did not believe you could sink so low'. The song's structure is familiar: a basic beat at 0:16, guitars building from 0:31 to sneering vocals, a 2:03 counter-riff that merges at 2:19 with vocals and ascending to the final verse and 3:26 final distortion... "La Mer" is the first major surprise, a beautiful and sweeping fusion of piano, keyboard and cello, reminiscent of Symbolist composer Debussy. At 1:07 Denise Milfort whispers, setting the stage for sometime Ministry drummer Bill Reiflin's jazz drumming at 1:22, and a funky 1:32 guitar/bass line. The pulsing synth guitar at 2:04 serves as anchoring percussion for a cinematic electronica mindscape, filtered through new layers of sonic chiaroscuro at 2:51. 3:06 phase shifting, 3:22 layer doubling, 3:37 outgoing solo, 3:50-3:54 more swirling vocal fragments, seguing into a fading cello quartet as shadows creep. David Carson's moody film-clip captures the end more ominously, depicting the beauty of drowning. This track contains the line 'Nothing can stop me now', which appears to be Reznor's personal mantra. This track rivals 'Hurt' and 'A Warm Place' from The Downward Spiral and 'Something I Can Never Have' from Pretty Hate Machine as perhaps the most emotionally revealing and delicate material that Reznor has written. "The Great Below" ends the first disc with more multi-layered textures fusing nostalgia and reverie: a twelve-second cello riff is counter-pointed by a plucked overlay, which builds to a 0:43 washed pulse effect, transformed by six second pulses between 1:04-1:19 and a further effects layer at 1:24. E-bow effects underscore lyrics like 'Currents have their say' (2:33) and 'Washes me away' (2:44), which a 3:33 sitar riff answers. These complexities are further transmuted by seemingly random events -- a 4:06 doubling of the sitar riff which 'glitches' and a 4:32 backbeat echo that drifts for four bars. While Reznor's lyrics suggest that he is unable to control subjective time-states (like The Joker in the Batman: Dark Knight series of Kali-yuga comic-books), the track constructions show that the Key to his hold over the listener is very carefully constructed songs whose spaces resemble Pythagorean mathematical formulas. Misdirecting the audience is the secret of many magicians. "The Way Out Is Through" opens the 'Right' disc with an industrial riff that builds at 0:19 to click-track and rhythm, the equivalent of a weaving spiral. Whispering 'All I've undergone/I will keep on' at 1:24, Reznor is backed at 1:38 by synths and drums coalescing into guitars, which take shape at 1:46 and turn into a torrential electrical current. The models are clearly natural morphogenetic structures. The track twists through inner storms and torments from 2:42 to 2:48, mirrored by vocal shards at 2:59 and soundscapes at 3:45, before piano fades in and out at 4:12. The title references peri-natal theories of development (particularly those of Stanislav Grof), which is the source of much of the album's imagery. "Into the Void" is not the Black Sabbath song of the same name, but a catchy track that uses the same unfolding formula (opening static, cello at 0:18, guitars at 0:31, drums and backbeat at 1:02, trademark industrial vocals and synth at 1:02, verse at 1:23), and would not appear out of place in a Survival Research Laboratories exhibition. At 3:42 Reznor plays with the edge of synth soundscapes, merging vocals at 4:02 and ending the track nicely at 4:44 alone. "Where Is Everybody?" emulates earlier structures, but relies from 2:01 on whirring effects and organic rhythms, including a flurry of eight beat pulses between 2:40-2:46 and a 3:33 spiralling guitar solo. The 4:26 guitar solo is pure Adrian Belew, and is suddenly ended by spluttering static and white noise at 5:13. "The Mark Has Been Made" signals another downshift into introspectiveness with 0:32 ghostly synth shimmers, echoed by cello at 1:04 which is the doubled at 1:55 by guitar. At 2:08 industrial riffs suddenly build up, weaving between 3:28 distorted guitars and the return of the repressed original layer at 4:16. The surprise is a mystery 32 second soundscape at the end with Reznor crooning 'I'm getting closer, all the time' like a zombie devil Elvis. "Please" highlights spacious noise at 0:48, and signals a central album motif at 1:04 with the line 'Time starts slowing down/Sink until I drown'. The psychic mood of the album shifts with the discovery of Imagination as a liberating force against oppression. The synth sound again is remarkably organic for an industrial album. "Starfuckers Inc" is the now infamous sneering attack on rock-stardom, perhaps at Marilyn Manson (at 3:08 Reznor quotes Carly Simon's 'You're So Vain'). Jungle beats and pulsing synths open the track, which features the sound-sculpting talent of Pop Will Eat Itself member Clint Mansell. Beginning at 0:26, Reznor's vocals appear to have been sampled, looped and cut up (apologies to Brion Gysin and William S. Burroughs). The lines 'I have arrived and this time you should believe the hype/I listened to everyone now I know everyone was right' is a very savage and funny exposure of Manson's constant references to Friedrich Nietzsche's Herd-mentality: the Herd needs a bogey-man to whip it into submission, and Manson comes dangerous close to fulfilling this potential, thus becoming trapped by a 'Stacked Deck' paradox. The 4:08 lyric line 'Now I belong I'm one of the Chosen Ones/Now I belong I'm one of the Beautiful Ones' highlights the problem of being Elect and becoming intertwined with institutionalised group-think. The album version ditches the closing sample of Gene Simmons screaming "Thankyou and goodnight!" to an enraptured audience on the single from KISS Alive (1975), which was appropriately over-the-top (the alternate quiet version is worth hearing also). "The danger Marilyn Manson faces", notes Don Webb (current High Priest of the Temple of Set), "is that he may end up in twenty years time on the 'Tonight Show' safely singing our favourite songs like a Goth Frank Sinatra, and will have gradually lost his antinomian power. It's much harder to maintain the enigmatic aura of an Evil villain than it is to play the clown with society". Reznor's superior musicianship and sense of irony should keep him from falling into the same trap. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "Complication" juggernauts in at 0:57 with screaming vocals and a barrage of white noise at 1:56. It's clear by now that Reznor has read his psychological operations (PSYOP) manuals pertaining to blasting the hell out of his audiences' psyche by any means necessary. Computer blip noise and black light flotation tank memories. Dislocating pauses and time-bends. The aural equivalent of Klein bottles. "The Big Come Down" begins with a four-second synth/static intro that is smashed apart by a hard beat at 0:05 and kaleidoscope guitars at 0:16. Critics refer to the song's lyrics in an attempt to project a narcissistic Reznor personality, but don't comment on stylistic tweaks like the AM radio influenced backing vocals at 1:02 and 1:19, or the use of guitars as a percussion layer at 1:51. A further intriguing element is the return of the fly samples at 2:38, an effect heard on previous releases and a possible post-human sub-text. The alien mythos will eventually reign over the banal and empty human. At 3:07 the synths return with static, a further overlay adds more synths at 3:45 as the track spirals to its peak, before dissipating at 3:1 in a mesh of percussion and guitars. "Underneath It All" opens with a riff that signals we have reached the album's climatic turning point, with the recurring theme of fragmenting body-memories returning at 0:23 with the line 'All I can do/I can still feel you', and being echoed by pulsing static at 0:42 as electric percussion. A 'Messiah Complex' appears at 1:34 with the line 'Crucify/After all I've died/After all I've tried/You are still inside', or at least it appears to be that on the surface. This is the kind of line that typical rock critics will quote, but a careful re-reading suggests that Reznor is pointing to the painful nature of remanifesting. Our past shapes us more than we would like to admit particularly our first relationships. "Ripe (With Decay)" is the album's final statement, a complex weaving of passages over a repetitive mesh of guitars, pulsing echoes, back-beats, soundscapes, and a powerful Mike Garson piano solo (2:26). Earlier motifs including fly samples (3:00), mournful funeral violas (3:36) and slowing time effects (4:28) recur throughout the track. Having finally reached the psychotic core, Reznor is not content to let us rest, mixing funk bass riffs (4:46), vocal snatches (5:23) and oscillating guitars (5:39) that drag the listener forever onwards towards the edge of the abyss (5:58). The final sequence begins at 6:22, loses fidelity at 6:28, and ends abruptly at 6:35. At millennium's end there is a common-held perception that the world is in an irreversible state of decay, and that Culture is just a wafer-thin veneer over anarchy. Music like The Fragile suggests that we are still trying to assimilate into popular culture the 'war-on-Self' worldviews unleashed by the nineteenth-century 'Masters of Suspicion' (Charles Darwin, Sigmund Freud, Friedrich Nietzsche). This 'assimilation gap' is evident in industrial music, which in the late 1970s was struggling to capture the mood of the Industrial Revolution and Charles Dickens, so the genre is ripe for further exploration of the scarred psyche. What the self-appointed moral guardians of the Herd fail to appreciate is that as the imprint baseline rises (reflective of socio-political realities), the kind of imagery prevalent throughout The Fragile and in films like Strange Days (1995), The Matrix (1999) and eXistenZ (1999) is going to get even darker. The solution is not censorship or repression in the name of pleasing an all-saving surrogate god-figure. No, these things have to be faced and embraced somehow. Such a process can only occur if there is space within for the Sadeian aesthetic that Nine Inch Nails embodies, and not a denial of Dark Eros. "We need a second Renaissance", notes Don Webb, "a rejuvenation of Culture on a significant scale". In other words, a global culture-shift of quantum (aeon or epoch-changing) proportions. The tools required will probably not come just from the over-wordy criticism of Cyber-culture and Cultural Studies or the logical-negative feeding frenzy of most Music Journalism. They will come from a dynamic synthesis of disciplines striving toward a unity of knowledge -- what socio-biologist Edward O. Wilson has described as 'Consilience'. Liberating tools and ideas will be conveyed to a wider public audience unfamiliar with such principles through predominantly science fiction visual imagery and industrial/electronica music. The Fragile serves as an invaluable model for how such artefacts could transmit their dreams and propagate their messages. For the hyper-alert listener, it will be the first step on a new journey. But sadly for the majority, it will be just another hysterical industrial album promoted as selection of the month. References Bester, Alfred. The Stars My Destination. London: Millennium Books, 1999. Eshun, Kodwo. More Brilliant than the Sun: Adventures in Sonic Fiction. London: Quartet Books, 1998. Van der Kolk, Bessel A. "Trauma and Memory." Traumatic Stress: The Effects of Overwhelming Experience on Mind, Body, and Society. Eds. Bessel A. van der Kolk et al. New York: Guilford Press, 1996. Nine Inch Nails. Downward Spiral. Nothing/Interscope, 1994. ---. The Fragile. Nothing, 1999. ---. Pretty Hate Machine. TVT, 1989. Citation reference for this article MLA style: Alex Burns. "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile." M/C: A Journal of Media and Culture 2.8 (1999). [your date of access] <http://www.uq.edu.au/mc/9912/nine.php>. Chicago style: Alex Burns, "'This Machine Is Obsolete': A Listeners' Guide to Nine Inch Nails' The Fragile," M/C: A Journal of Media and Culture 2, no. 8 (1999), <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]). APA style: Alex Burns. (1999) 'This machine is obsolete': a listeners' guide to Nine Inch Nails' The fragile. M/C: A Journal of Media and Culture 2(8). <http://www.uq.edu.au/mc/9912/nine.php> ([your date of access]).